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Ogawa A, Izumikawa K, Tate S, Isoyama S, Mori M, Fujiwara K, Watanabe S, Ohga T, Jo U, Taniyama D, Kitajima S, Tanaka S, Onji H, Kageyama SI, Yamamoto G, Saito H, Morita TY, Okada M, Natsumeda M, Nagahama M, Kobayashi J, Ohashi A, Sasanuma H, Higashiyama S, Dan S, Pommier Y, Murai J. SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis. Mol Cell 2025; 85:894-912.e10. [PMID: 39909041 PMCID: PMC11890970 DOI: 10.1016/j.molcel.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 12/11/2024] [Accepted: 01/10/2025] [Indexed: 02/07/2025]
Abstract
Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis in response to replication stress. SLFN11's Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.
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Affiliation(s)
- Akane Ogawa
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan
| | - Keiichi Izumikawa
- Laboratory of Molecular and Cellular Biochemistry, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
| | - Sota Tate
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Ehime 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Sho Isoyama
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Masaru Mori
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan
| | - Kohei Fujiwara
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Soyoka Watanabe
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan
| | - Takayuki Ohga
- Laboratory of Molecular and Cellular Biochemistry, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
| | - Ukhyun Jo
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20814, USA
| | - Daiki Taniyama
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20814, USA
| | - Shojiro Kitajima
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan
| | - Soichiro Tanaka
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan
| | - Hiroshi Onji
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Shun-Ichiro Kageyama
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Chiba 277-8577, Japan
| | - Gaku Yamamoto
- Division of Collaborative Research and Development, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
| | - Hitoshi Saito
- Division of Collaborative Research and Development, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
| | - Tomoko Yamamori Morita
- Division of Collaborative Research and Development, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
| | - Masayasu Okada
- Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Brain Tumor Biology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
| | - Manabu Natsumeda
- Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Advanced Treatment of Neurological Diseases Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
| | - Masami Nagahama
- Laboratory of Molecular and Cellular Biochemistry, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
| | - Junya Kobayashi
- Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan; Department of Radiological Sciences, School of Health Sciences at Narita, International University of Health and Welfare, Narita, Tokyo 286-0048, Japan
| | - Akihiro Ohashi
- Division of Collaborative Research and Development, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
| | - Hiroyuki Sasanuma
- Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-0057, Japan
| | - Shigeki Higashiyama
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Ehime 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; Department of Oncogenesis and Tumor Regulation, Osaka International Cancer Institute, Osaka 103-0027, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20814, USA.
| | - Junko Murai
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan; Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Ehime 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
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Pratama S, Wiyono L, Setiawan MS, Lauren BC. PARP inhibitors as therapy for small cell lung carcinoma: A systematic review and meta-analysis of clinical trials. Cancer Treat Res Commun 2025; 42:100874. [PMID: 39892078 DOI: 10.1016/j.ctarc.2025.100874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 01/05/2025] [Accepted: 01/23/2025] [Indexed: 02/03/2025]
Abstract
BACKGROUND Small Cell Lung Cancer (SCLC) is a neuroendocrine carcinoma characterized by aggressive behavior and poor prognosis with limited treatment options. Poly ADP-Ribose Polymerase inhibitors (PARPi) are novel anti-cancer agents that induce DNA damages and cause cell death in tumor cells with impaired DNA repair, known as the synthetic lethality concept. This study aimed to analyze the efficacy and safety of PARPi for patients with SCLC from available clinical trial data. METHODS Studies reporting efficacy and safety of PARPi therapy for SCLC patients were searched across five databases with predetermined eligibility criteria in accordance with the PRISMA statement. Critical appraisal was done using suitable tools, outcomes were extracted, and analyzed. RESULTS Five randomized controlled clinical trials with 451 interventional patients and 308 control patients with SCLC were included. The analysis showed increased Progression-Free Survival (PFS) (RR 0.92 (95 %CI 0.84-1.00; p=0.05)) and Objective Response Rate (ORR) (RR 1.27 (95 %CI 1.07-1.50; p=0.007)), no significant difference in Overall Survival (OS) (RR 1.03 (95 %CI 0.92-1.15; p=0.60)), and an increased risk for serious Treatment Emergent Adverse Events (TEAEs) (RR 1.13 (95 %CI 0.95-1.35; p=0.16)) in PARPi-receiving SCLC patients. Amongst the hematologic toxicities, sub-analysis showed that thrombocytopenia had the highest risk, followed by neutropenia, anemia, leukopenia, and lymphopenia. CONCLUSION The addition of PARPi in the chemotherapy regimen for patients with SCLC results in increased PFS and ORR, with no difference in OS and an increased risk of TEAEs. Further and larger clinical studies are needed to validate the efficacy and safety of PARPi therapy for SCLC patients.
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Affiliation(s)
- Samuel Pratama
- Dr Abdul Aziz General Hospital, Singkawang City, West Borneo Province, Indonesia; Faculty of Medicine, University of Indonesia, Jakarta, Indonesia.
| | - Lowilius Wiyono
- Dr Abdul Aziz General Hospital, Singkawang City, West Borneo Province, Indonesia; Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Martien Silviandy Setiawan
- Dr Abdul Aziz General Hospital, Singkawang City, West Borneo Province, Indonesia; Faculty of Medicine, Pelita Harapan University, Banten, Indonesia
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Kanagavalli P, Elkaffas RA, Mohideen MIH, Eissa S. Electrochemical immunosensor for the predictive cancer biomarker SLFN11 using reduced graphene oxide/MIL-101(Cr)-NH 2 composite. Int J Biol Macromol 2025; 285:138174. [PMID: 39626816 DOI: 10.1016/j.ijbiomac.2024.138174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/05/2024] [Accepted: 11/27/2024] [Indexed: 12/06/2024]
Abstract
SLFN11 is a predictive cancer biomarker essential for identifying tumors that are sensitive to DNA-damaging agents, facilitating more personalized and effective treatment approaches. Detecting this biomarker can guide therapeutic decisions and improve outcomes for cancer patients. However, existing detection methods for SLFN11 are complex and require advanced techniques. In this study, we introduce the first immunosensor designed for on-site detection of SLFN11. An advanced electrochemical immunosensor platform utilizing a composite of graphene oxide (GO) and chromium-based metal organic framework (MIL-101 (Cr)-NH2) was developed. The integration of GO and MIL-101(Cr)-NH2 was characterized through FT-IR, XRD, SEM, and XPS, affirming the formation of the composite. The subsequent electrochemical reduction to rGO/MIL-101(Cr)-NH2 significantly improved the electrochemical performance and stability. A glutaraldehyde cross-linker was then utilized to attach the SLFN11-specific antibody to the amine groups of the MOF-modified electrodes. This led to the development of rapid, sensitive, portable, and cost-effective immunosensor for SLFN11 at concentrations as low as 8.9 pg/mL which holds promise for early cancer diagnosis. High specificity was achieved, with minimal cross-reactivity observed with other cancer biomarkers such as pepsinogen I, claudin 18.2 and Programmed cell death protein 1. Demonstrating practical applicability, the electrochemical immunosensor validated by commercial ELISA kit showed successful detection in serum samples with high recovery rates and reproducibility. This research highlights the potential of rGO/MOFs composites in electrochemical biosensors developments for early cancer diagnostics and personalized medicine.
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Affiliation(s)
- Pandiyaraj Kanagavalli
- Department of Chemistry, Khalifa University of Science and Technology, Abu Dhabi, P.O. Box 127788, United Arab Emirates
| | - Ragi Adham Elkaffas
- Department of Chemistry, Khalifa University of Science and Technology, Abu Dhabi, P.O. Box 127788, United Arab Emirates
| | - M Infas H Mohideen
- Department of Chemistry, Khalifa University of Science and Technology, Abu Dhabi, P.O. Box 127788, United Arab Emirates; Center for Catalysis and Separations, Khalifa University of Science and Technology, Abu Dhabi, P.O. Box 127788, United Arab Emirates
| | - Shimaa Eissa
- Department of Chemistry, Khalifa University of Science and Technology, Abu Dhabi, P.O. Box 127788, United Arab Emirates; Center for Catalysis and Separations, Khalifa University of Science and Technology, Abu Dhabi, P.O. Box 127788, United Arab Emirates.
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Kugler M, Metzner FJ, Witte G, Hopfner KP, Lammens K. Phosphorylation-mediated conformational change regulates human SLFN11. Nat Commun 2024; 15:10500. [PMID: 39627193 PMCID: PMC11615386 DOI: 10.1038/s41467-024-54833-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024] Open
Abstract
Human Schlafen 11 (SLFN11) is sensitizing cells to DNA damaging agents by irreversibly blocking stalled replication forks, making it a potential predictive biomarker in chemotherapy. Furthermore, SLFN11 acts as a pattern recognition receptor for single-stranded DNA (ssDNA) and functions as an antiviral restriction factor, targeting translation in a codon-usage-dependent manner through its endoribonuclease activity. However, the regulation of the various SLFN11 functions and enzymatic activities remains enigmatic. Here, we present cryo-electron microscopy (cryo-EM) structures of SLFN11 bound to tRNA-Leu and tRNA-Met that give insights into tRNA binding and cleavage, as well as its regulation by phosphorylation at S219 and T230. SLFN11 phosphomimetic mutant S753D adopts a monomeric conformation, shows ATP binding, but loses its ability to bind ssDNA and shows reduced ribonuclease activity. Thus, the phosphorylation site S753 serves as a conformational switch, regulating SLFN11 dimerization, as well as ATP and ssDNA binding, while S219 and T230 regulate tRNA recognition and nuclease activity.
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Affiliation(s)
- Michael Kugler
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, 81377, Munich, Germany
| | - Felix J Metzner
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, 81377, Munich, Germany
| | - Gregor Witte
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, 81377, Munich, Germany
| | - Karl-Peter Hopfner
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, 81377, Munich, Germany
| | - Katja Lammens
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, 81377, Munich, Germany.
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König P, Eichhorn JM, Suparman E, Bückreiß N, Cinatl J, Michaelis M, Bendas G. SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167448. [PMID: 39117290 DOI: 10.1016/j.bbadis.2024.167448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and KuramochirCDDP2000. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.
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Affiliation(s)
- Philipp König
- Department of Pharmacy, University Bonn, 53121 Bonn, Germany
| | | | - Eloy Suparman
- Department of Pharmacy, University Bonn, 53121 Bonn, Germany
| | - Nico Bückreiß
- Department of Pharmacy, University Bonn, 53121 Bonn, Germany
| | - Jindrich Cinatl
- Institute of Medical Virology, University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany; Interdisciplinary Laboratory for Paediatric Tumour and Virus Research, Dr. Petra Joh Research Institute, 60528 Frankfurt am Main, Germany
| | - Martin Michaelis
- Interdisciplinary Laboratory for Paediatric Tumour and Virus Research, Dr. Petra Joh Research Institute, 60528 Frankfurt am Main, Germany; School of Biosciences, Division of Natural Sciences, University of Kent, Canterbury, Kent CT2 7NJ, UK
| | - Gerd Bendas
- Department of Pharmacy, University Bonn, 53121 Bonn, Germany.
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Mu A, Okamoto Y, Katsuki Y, Takata M. The role of SLFN11 in DNA replication stress response and its implications for the Fanconi anemia pathway. DNA Repair (Amst) 2024; 141:103733. [PMID: 39096698 DOI: 10.1016/j.dnarep.2024.103733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 05/26/2024] [Accepted: 07/19/2024] [Indexed: 08/05/2024]
Abstract
Fanconi anemia (FA) is a hereditary disorder characterized by a deficiency in the repair of DNA interstrand crosslinks and the response to replication stress. Endogenous DNA damage, most likely caused by aldehydes, severely affects hematopoietic stem cells in FA, resulting in progressive bone marrow failure and the development of leukemia. Recent studies revealed that expression levels of SLFN11 affect the replication stress response and are a strong determinant in cell killing by DNA-damaging cancer chemotherapy. Because SLFN11 is highly expressed in the hematopoietic system, we speculated that SLFN11 may have a significant role in FA pathophysiology. Indeed, we found that DNA damage sensitivity in FA cells is significantly mitigated by the loss of SLFN11 expression. Mechanistically, we demonstrated that SLFN11 destabilizes the nascent DNA strands upon replication fork stalling. In this review, we summarize our work regarding an interplay between SLFN11 and the FA pathway, and the role of SLFN11 in the response to replication stress.
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Affiliation(s)
- Anfeng Mu
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan.
| | - Yusuke Okamoto
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoko Katsuki
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Minoru Takata
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan.
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7
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Onji H, Tate S, Sakaue T, Fujiwara K, Nakano S, Kawaida M, Onishi N, Matsumoto T, Yamagami W, Sugiyama T, Higashiyama S, Pommier Y, Kobayashi Y, Murai J. Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks. Oncogene 2024; 43:2475-2489. [PMID: 38961202 PMCID: PMC11315672 DOI: 10.1038/s41388-024-03094-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 06/17/2024] [Accepted: 06/26/2024] [Indexed: 07/05/2024]
Abstract
The preferential response to PARP inhibitors (PARPis) in BRCA-deficient and Schlafen 11 (SLFN11)-expressing ovarian cancers has been documented, yet the underlying molecular mechanisms remain unclear. As the accumulation of single-strand DNA (ssDNA) gaps behind replication forks is key for the lethality effect of PARPis, we investigated the combined effects of SLFN11 expression and BRCA deficiency on PARPi sensitivity and ssDNA gap formation in human cancer cells. PARPis increased chromatin-bound RPA2 and ssDNA gaps in SLFN11-expressing cells and even more in cells with BRCA1 or BRCA2 deficiency. SLFN11 was co-localized with chromatin-bound RPA2 under PARPis treatment, with enhanced recruitment in BRCA2-deficient cells. Notably, the chromatin-bound SLFN11 under PARPis did not block replication, contrary to its function under replication stress. SLFN11 recruitment was attenuated by the inactivation of MRE11. Hence, under PARPi treatment, MRE11 expression and BRCA deficiency lead to ssDNA gaps behind replication forks, where SLFN11 binds and increases their accumulation. As ovarian cancer patients who responded (progression-free survival >2 years) to olaparib maintenance therapy had a significantly higher SLFN11-positivity than short-responders (<6 months), our findings provide a mechanistic understanding of the favorable responses to PARPis in SLFN11-expressing and BRCA-deficient tumors. It highlight the clinical implications of SLFN11.
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Affiliation(s)
- Hiroshi Onji
- Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Sota Tate
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Toon, Ehime, Japan
| | - Tomohisa Sakaue
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Toon, Ehime, Japan
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Kohei Fujiwara
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
| | - Shiho Nakano
- Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Miho Kawaida
- Division of Diagnostic Pathology, Keio University Hospital, Shinjuku-ku, Tokyo, Japan
| | - Nobuyuki Onishi
- Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Shinagawa-ku, Tokyo, Japan
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takashi Matsumoto
- Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Wataru Yamagami
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takashi Sugiyama
- Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Shigeki Higashiyama
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Toon, Ehime, Japan
- Department of Oncogenesis and Tumor Regulation, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Yusuke Kobayashi
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
- Department of Obstetrics and Gynecology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Junko Murai
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Toon, Ehime, Japan.
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
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Scattolin D, Maso AD, Ferro A, Frega S, Bonanno L, Guarneri V, Pasello G. The emerging role of Schlafen-11 (SLFN11) in predicting response to anticancer treatments: Focus on small cell lung cancer. Cancer Treat Rev 2024; 128:102768. [PMID: 38797062 DOI: 10.1016/j.ctrv.2024.102768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
Small cell lung cancer (SCLC) is characterized by a dismal prognosis. Many efforts have been made so far for identifying novel biomarkers for a personalized treatment for SCLC patients. Schlafen 11 (SLFN11) is a protein differently expressed in many cancers and recently emerged as a new potential biomarker. Lower expression of SLFN11 correlates with a worse prognosis in SCLC and other tumors. SLFN11 has a role in tumorigenesis, inducing replication arrest in the presence of DNA damage through the block of the replication fork. SLFN11 interacts also with chromatin accessibility, proteotoxic stress and mammalian target of rapamycin signalling pathway. The expression of SLFN11 is regulated by epigenetic mechanisms, including promoter methylation, histone deacetylation, and the histone methylation. The downregulation of SLFN11 correlates with a worse response to topoisomerase I and II inhibitors, alkylating agents, and poly ADP-ribose polymerase inhibitors in different cancer types. Some studies exploring strategies for overcoming drug resistance in tumors with low levels of SLFN11 showed promising results. One of these strategies includes the interaction with the Ataxia Telangiectasia and Rad3-related pathway, constitutively activated and leading to cell survival and tumor growth in the presence of low levels of SLFN11. Furthermore, the expression of SLFN11 is dynamic through time and different anticancer therapy and liquid biopsy seems to be an attractive tool for catching SLFN11 different expressions. Despite this, further investigations exploring SLFN11 as a predictive biomarker, its longitudinal changes, and new strategies to overcome drug resistances are needed.
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Affiliation(s)
- Daniela Scattolin
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | | - Alessandra Ferro
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Stefano Frega
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Laura Bonanno
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Valentina Guarneri
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Giulia Pasello
- Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
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9
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Zhang P, Hu X, Li Z, Liu Q, Liu L, Jin Y, Liu S, Zhao X, Wang J, Hao D, Chen H, Liu D. Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA. Sci Immunol 2024; 9:eadj5465. [PMID: 38875319 DOI: 10.1126/sciimmunol.adj5465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 05/16/2024] [Indexed: 06/16/2024]
Abstract
Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif-dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA-induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.
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Affiliation(s)
- Peng Zhang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Xiaoqing Hu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Zekun Li
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Qian Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Lele Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Yingying Jin
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Sizhe Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Xiang Zhao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Jianqiao Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Delong Hao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Houzao Chen
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Depei Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Tianjin 300301, China
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10
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Jäger N, Pöhlmann S, Rodnina MV, Ayyub SA. Interferon-Stimulated Genes that Target Retrovirus Translation. Viruses 2024; 16:933. [PMID: 38932225 PMCID: PMC11209297 DOI: 10.3390/v16060933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/27/2024] [Accepted: 06/01/2024] [Indexed: 06/28/2024] Open
Abstract
The innate immune system, particularly the interferon (IFN) system, constitutes the initial line of defense against viral infections. IFN signaling induces the expression of interferon-stimulated genes (ISGs), and their products frequently restrict viral infection. Retroviruses like the human immunodeficiency viruses and the human T-lymphotropic viruses cause severe human diseases and are targeted by ISG-encoded proteins. Here, we discuss ISGs that inhibit the translation of retroviral mRNAs and thereby retrovirus propagation. The Schlafen proteins degrade cellular tRNAs and rRNAs needed for translation. Zinc Finger Antiviral Protein and RNA-activated protein kinase inhibit translation initiation factors, and Shiftless suppresses translation recoding essential for the expression of retroviral enzymes. We outline common mechanisms that underlie the antiviral activity of multifunctional ISGs and discuss potential antiretroviral therapeutic approaches based on the mode of action of these ISGs.
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Affiliation(s)
- Niklas Jäger
- Infection Biology Unit, German Primate Center—Leibniz Institute for Primate Research, 37077 Göttingen, Germany; (N.J.); (S.P.)
- Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center—Leibniz Institute for Primate Research, 37077 Göttingen, Germany; (N.J.); (S.P.)
- Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany
| | - Marina V. Rodnina
- Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany;
| | - Shreya Ahana Ayyub
- Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany;
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11
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Trillo Aliaga P, Del Signore E, Fuorivia V, Spitaleri G, Asnaghi R, Attili I, Corvaja C, Carnevale Schianca A, Passaro A, de Marinis F. The Evolving Scenario of ES-SCLC Management: From Biology to New Cancer Therapeutics. Genes (Basel) 2024; 15:701. [PMID: 38927637 PMCID: PMC11203015 DOI: 10.3390/genes15060701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/13/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.
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Affiliation(s)
- Pamela Trillo Aliaga
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Ester Del Signore
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Valeria Fuorivia
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Gianluca Spitaleri
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Riccardo Asnaghi
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Ilaria Attili
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Carla Corvaja
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Ambra Carnevale Schianca
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
| | - Filippo de Marinis
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141 Milan, Italy
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12
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Boon NJ, Oliveira RA, Körner PR, Kochavi A, Mertens S, Malka Y, Voogd R, van der Horst SEM, Huismans MA, Smabers LP, Draper JM, Wessels LFA, Haahr P, Roodhart JML, Schumacher TNM, Snippert HJ, Agami R, Brummelkamp TR. DNA damage induces p53-independent apoptosis through ribosome stalling. Science 2024; 384:785-792. [PMID: 38753784 DOI: 10.1126/science.adh7950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/11/2024] [Indexed: 05/18/2024]
Abstract
In response to excessive DNA damage, human cells can activate p53 to induce apoptosis. Cells lacking p53 can still undergo apoptosis upon DNA damage, yet the responsible pathways are unknown. We observed that p53-independent apoptosis in response to DNA damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed translation initiation. A genetic screen identified the transfer RNAse SLFN11 and the kinase GCN2 as factors required for UUA stalling and global translation inhibition, respectively. Stalled ribosomes activated a ribotoxic stress signal conveyed by the ribosome sensor ZAKα to the apoptosis machinery. These results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.
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Affiliation(s)
- Nicolaas J Boon
- Oncode Institute, Utrecht, Netherlands
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Rafaela A Oliveira
- Oncode Institute, Utrecht, Netherlands
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Pierré-René Körner
- Oncode Institute, Utrecht, Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Adva Kochavi
- Oncode Institute, Utrecht, Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Sander Mertens
- Oncode Institute, Utrecht, Netherlands
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Yuval Malka
- Oncode Institute, Utrecht, Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Rhianne Voogd
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Suzanne E M van der Horst
- Oncode Institute, Utrecht, Netherlands
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Maarten A Huismans
- Oncode Institute, Utrecht, Netherlands
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Lidwien P Smabers
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Jonne M Draper
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Lodewyk F A Wessels
- Oncode Institute, Utrecht, Netherlands
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Peter Haahr
- Oncode Institute, Utrecht, Netherlands
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands
- Center for Gene Expression, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jeanine M L Roodhart
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Ton N M Schumacher
- Oncode Institute, Utrecht, Netherlands
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Hugo J Snippert
- Oncode Institute, Utrecht, Netherlands
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Reuven Agami
- Oncode Institute, Utrecht, Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Thijn R Brummelkamp
- Oncode Institute, Utrecht, Netherlands
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands
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13
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Zhou J, Zhang MY, Gao AA, Zhu C, He T, Herman JG, Guo MZ. Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor. World J Gastrointest Oncol 2024; 16:2060-2073. [PMID: 38764821 PMCID: PMC11099458 DOI: 10.4251/wjgo.v16.i5.2060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/26/2024] [Accepted: 04/01/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear. AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects. METHODS To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model. RESULTS Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo. CONCLUSION SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.
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Affiliation(s)
- Jing Zhou
- School of Medicine, NanKai University, Tianjin 300071, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Mei-Ying Zhang
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Ai-Ai Gao
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Cheng Zhu
- School of Medicine, NanKai University, Tianjin 300071, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Tao He
- Departments of Pathology, Characteristic Medical Center of The Chinese People’s Armed Police Force, Tianjin 300162, China
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, United States
| | - Ming-Zhou Guo
- School of Medicine, NanKai University, Tianjin 300071, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China
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14
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Perez RE, Eckerdt F, Platanias LC. Schlafens: Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:1805. [PMID: 38791884 PMCID: PMC11119473 DOI: 10.3390/cancers16101805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/02/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
The interferon (IFN) family of immunomodulatory cytokines has been a focus of cancer research for over 50 years with direct and indirect implications in cancer therapy due to their properties to inhibit malignant cell proliferation and modulate immune responses. Among the transcriptional targets of the IFNs is a family of genes referred to as Schlafens. The products of these genes, Schlafen proteins, exert important roles in modulating cellular proliferation, differentiation, immune responses, viral replication, and chemosensitivity of malignant cells. Studies have demonstrated that abnormal expression of various Schlafens contributes to the pathophysiology of various cancers. Schlafens are now emerging as promising biomarkers and potentially attractive targets for drug development in cancer research. Here, we highlight research suggesting the use of Schlafens as cancer biomarkers and the rationale for the development of specific drugs targeting Schlafen proteins.
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Affiliation(s)
- Ricardo E. Perez
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA; (R.E.P.); (F.E.)
- Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Frank Eckerdt
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA; (R.E.P.); (F.E.)
- Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Leonidas C. Platanias
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA; (R.E.P.); (F.E.)
- Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA
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15
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Park S, Kim YJ, Min YJ, Mortimer PGS, Kim HJ, Smith SA, Dean E, Jung HA, Sun JM, Park WY, Ahn JS, Ahn MJ, Lee SH, Park K. Biomarker-driven phase 2 umbrella trial: Clinical efficacy of olaparib monotherapy and combination with ceralasertib (AZD6738) in small cell lung cancer. Cancer 2024; 130:541-552. [PMID: 37843249 DOI: 10.1002/cncr.35059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/27/2023] [Accepted: 08/07/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND Based on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)-related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR-targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated. METHODS As part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum-based regimens were allocated to the olaparib monotherapy arm and nonbiomarker-selected patients were allocated to the olaparib and ceralasertib combination arm. RESULTS In the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression-free survival was 1.3 months (95% CI, 1.2-NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression-free survival was 2.8 months (95% CI, 1.8-5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm. CONCLUSIONS Targeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.
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Affiliation(s)
- Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yu Jung Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Young Joo Min
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | | | - Hee-Jung Kim
- External R&D, R&D Oncology, AstraZeneca, Seoul, Korea
| | | | - Emma Dean
- R&D Oncology, AstraZeneca, Cambridge, UK
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jong-Mu Sun
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Woong-Yang Park
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se-Hoon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Keunchil Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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16
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Fujiwara K, Maekawa M, Iimori Y, Ogawa A, Urano T, Kono N, Takeda H, Higashiyama S, Arita M, Murai J. The crucial role of single-stranded DNA binding in enhancing sensitivity to DNA-damaging agents for Schlafen 11 and Schlafen 13. iScience 2023; 26:108529. [PMID: 38125019 PMCID: PMC10730379 DOI: 10.1016/j.isci.2023.108529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/19/2023] [Accepted: 11/20/2023] [Indexed: 12/23/2023] Open
Abstract
Schlafen (SLFN) 11 enhances cellular sensitivity to various DNA-damaging anticancer agents. Among the human SLFNs (SLFN5/11/12/13/14), SLFN11 is unique in its drug sensitivity and ability to block replication under DNA damage. In biochemical analysis, SLFN11 binds single-stranded DNA (ssDNA), and this binding is enhanced by the dephosphorylation of SLFN11. In this study, human cell-based assays demonstrated that a point mutation at the ssDNA-binding site of SLFN11 or a constitutive phosphorylation mutant abolished SLFN11-dependent drug sensitivity. Additionally, we discovered that nuclear SLFN13 with a point mutation mimicking the DNA-binding site of SLFN11 was recruited to chromatin, blocked replication, and enhanced drug sensitivity. Through generating multiple mutants and structure analyses of SLFN11 and SLFN13, we identified protein phosphatase 2A as a binding partner of SLFN11 and the putative binding motif in SLFN11. These findings provide crucial insights into the unique characteristics of SLFN11, contributing to a better understanding of its mechanisms.
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Affiliation(s)
- Kohei Fujiwara
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-Ku, Tokyo 105-8512, Japan
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
| | - Masashi Maekawa
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-Ku, Tokyo 105-8512, Japan
| | - Yuki Iimori
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
| | - Akane Ogawa
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
| | - Takeshi Urano
- Department of Biochemistry, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
- Center for Vaccines and Therapeutic Antibodies for Emerging Infectious Diseases, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Nobuaki Kono
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa 252-0882, Japan
| | - Hiroyuki Takeda
- Division of Proteo-Drug-Discovery, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan
| | - Shigeki Higashiyama
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Ehime 791-0295, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
- Department of Oncogenesis and Tumor Regulation, Osaka International Cancer Institute, Chuo-Ku, Osaka 541-8567, Japan
| | - Makoto Arita
- Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-Ku, Tokyo 105-8512, Japan
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
- Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo, Japan
- Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan
| | - Junko Murai
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Ehime 791-0295, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
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Raynaud CM, Ahmed EI, Jabeen A, Sanchez A, Sherif S, Carneiro-Lobo TC, Awad A, Awartani D, Naik A, Thomas R, Decock J, Zoppoli G, Bedongnetti D, Hendrickx WRL. Modulation of SLFN11 induces changes in DNA Damage response in breast cancer. Cancer Cell Int 2023; 23:291. [PMID: 38001424 PMCID: PMC10668346 DOI: 10.1186/s12935-023-03144-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Lack of Schlafen family member 11 (SLFN11) expression has been recently identified as a dominant genomic determinant of response to DNA damaging agents in numerous cancer types. Thus, several strategies aimed at increasing SLFN11 are explored to restore chemosensitivity of refractory cancers. In this study, we examined various approaches to elevate SLFN11 expression in breast cancer cellular models and confirmed a corresponding increase in chemosensitivity with using the most successful efficient one. As oncogenic transcriptomic downregulation is often driven by methylation of the promotor region, we explore the demethylation effect of 5-aza-2'-deoxycytidine (decitabine), on the SLFN11 gene. Since SLFN11 has been reported as an interferon inducible gene, and interferon is secreted during an active anti-tumor immune response, we investigated the in vitro effect of IFN-γ on SLFN11 expression in breast cancer cell lines. As a secondary approach to pick up cross talk between immune cells and SLFN11 expression we used indirect co-culture of breast cancer cells with activated PBMCs and evaluated if this can drive SLFN11 upregulation. Finally, as a definitive and specific way to modulate SLFN11 expression we implemented SLFN11 dCas9 (dead CRISPR associated protein 9) systems to specifically increase or decrease SLFN11 expression. RESULTS After confirming the previously reported correlation between methylation of SLFN11 promoter and its expression across multiple cell lines, we showed in-vitro that decitabine and IFN-γ could increase moderately the expression of SLFN11 in both BT-549 and T47D cell lines. The use of a CRISPR-dCas9 UNISAM and KRAB system could increase or decrease SLFN11 expression significantly (up to fivefold), stably and specifically in BT-549 and T47D cancer cell lines. We then used the modified cell lines to quantify the alteration in chemo sensitivity of those cells to treatment with DNA Damaging Agents (DDAs) such as Cisplatin and Epirubicin or DNA Damage Response (DDRs) drugs like Olaparib. RNAseq was used to elucidate the mechanisms of action affected by the alteration in SLFN11 expression. In cell lines with robust SLFN11 promoter methylation such as MDA-MB-231, no SLFN11 expression could be induced by any approach. CONCLUSION To our knowledge this is the first report of the stable non-lethal increase of SLFN11 expression in a cancer cell line. Our results show that induction of SLFN11 expression can enhance DDA and DDR sensitivity in breast cancer cells and dCas9 systems may represent a novel approach to increase SLFN11 and achieve higher sensitivity to chemotherapeutic agents, improving outcome or decreasing required drug concentrations. SLFN11-targeting therapies might be explored pre-clinically to develop personalized approaches.
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Affiliation(s)
| | - Eiman I Ahmed
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
- Department of Biomedical Science, College of Health Sciences, Qatar University, Doha, Qatar
| | - Ayesha Jabeen
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
| | - Apryl Sanchez
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
| | - Shimaa Sherif
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
| | | | - Amany Awad
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
| | - Dina Awartani
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
| | - Adviti Naik
- Translational Cancer and Immunity Center, Qatar Biomedical Research Center, Doha, Qatar
| | - Remy Thomas
- Translational Cancer and Immunity Center, Qatar Biomedical Research Center, Doha, Qatar
| | - Julie Decock
- Translational Cancer and Immunity Center, Qatar Biomedical Research Center, Doha, Qatar
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar
| | - Gabriele Zoppoli
- Department of Internal Medicine (DiMI), University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS per l'Oncologia, Genoa, Italy
| | - Davide Bedongnetti
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar
- Department of Internal Medicine (DiMI), University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy
- Clinical and Experimental Oncology and Hematology, Ospedale Policlinico San Martino, Genoa, Italy
| | - Wouter R L Hendrickx
- Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar.
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar.
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18
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Carlisle JW, Leal T. Advancing immunotherapy in small cell lung cancer. Cancer 2023; 129:3525-3534. [PMID: 37602492 DOI: 10.1002/cncr.34977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 08/22/2023]
Abstract
Small cell lung cancer (SCLC) is a rapidly progressive neuroendocrine carcinoma that, until recently, had a very small armamentarium of effective treatments. Advances in DNA sequencing and whole transcriptomics have delineated key subtypes; therefore, SCLC is no longer viewed as a homogeneous cancer. Chemoimmunotherapy with PD1 blockade is now the standard of care for advanced disease, and ongoing research efforts are moving this strategy into the limited stage setting. Combination strategies of immunotherapy with radiation are also under active clinical trial in both limited and extensive stage disease. PLAIN LANGUAGE SUMMARY: Small cell lung cancer (SCLC) is a rapidly progressive neuroendocrine carcinoma that, until recently, had a very small armamentarium of effective treatments. Chemoimmunotherapy with immune check point inhibitors is now the standard of care for advanced disease. This comprehensive review provides an overview of current treatment strategies for SCLC, unmet needs in this patient population, and emerging treatment strategies incorporating immunotherapy that will hopefully further improve outcomes for patients.
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Affiliation(s)
- Jennifer W Carlisle
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Ticiana Leal
- Department of Hematology and Medical Oncology, Thoracic Medical Oncology Program, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
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19
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Alvi E, Mochizuki AL, Katsuki Y, Ogawa M, Qi F, Okamoto Y, Takata M, Mu A. Mouse Slfn8 and Slfn9 genes complement human cells lacking SLFN11 during the replication stress response. Commun Biol 2023; 6:1038. [PMID: 37833372 PMCID: PMC10575959 DOI: 10.1038/s42003-023-05406-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
The Schlafen (SLFN)11 gene has been implicated in various biological processes such as suppression of HIV replication, replication stress response, and sensitization of cancer cells to chemotherapy. Due to the rapid diversification of the SLFN family members, it remains uncertain whether a direct ortholog of human SLFN11 exists in mice. Here we show that mSLFN8/9 and hSLFN11 were rapidly recruited to microlaser-irradiated DNA damage tracks. Furthermore, Slfn8/9 expression could complement SLFN11 loss in human SLFN11-/- cells, and as a result, reduced the growth rate to wild-type levels and partially restored sensitivity to DNA-damaging agents. In addition, both Slfn8/9 and SLFN11 expression accelerated stalled fork degradation and decreased RPA and RAD51 foci numbers after DNA damage. Based on these results, we propose that mouse Slfn8 and Slfn9 genes may share an orthologous function with human SLFN11. This notion may facilitate understanding of SLFN11's biological role through in vivo studies via mouse modeling.
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Affiliation(s)
- Erin Alvi
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Laboratory of Biochemical Cell Dynamics, Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Ayako L Mochizuki
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- CiRA Foundation, Kyoto, Japan
| | - Yoko Katsuki
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Minori Ogawa
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Fei Qi
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Yusuke Okamoto
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Minoru Takata
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan
| | - Anfeng Mu
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
- Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan.
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20
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Phan Z, Ford CE, Caldon CE. DNA repair biomarkers to guide usage of combined PARP inhibitors and chemotherapy: A meta-analysis and systematic review. Pharmacol Res 2023; 196:106927. [PMID: 37717683 DOI: 10.1016/j.phrs.2023.106927] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/17/2023] [Accepted: 09/13/2023] [Indexed: 09/19/2023]
Abstract
PURPOSE The addition of PARP inhibitors to chemotherapy has been assessed in > 80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy. METHODS A systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function (BRCA1, BRCA2, homologous recombination deficiency test, ATM, ERCC1, SLFN11). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance, and fixed or random effects modelling. Subgroup analyses were conducted on biomarker selection and type of malignancy. RESULTS Nine studies comprising 2547 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients with a DNA repair biomarker (HR: 0.57, 95% CI: 0.48-0.68, p < 0.00001), but there was no benefit in patients who lacked a biomarker (HR: 0.94, 95% CI: 0.82-1.08, p = 0.38). Subgroup analysis showed that BRCA status and SLFN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in ovarian, breast and small cell lung cancers. The addition of PARP inhibitors to chemotherapy was associated with increased grade 3/4 side effects, and particularly neutropenia. CONCLUSIONS Combination therapy only improves PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitise patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of altered DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as individual arms of treatment can also confer benefit.
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Affiliation(s)
- Zoe Phan
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
| | - Caroline E Ford
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - C Elizabeth Caldon
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
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21
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Qi F, Alvi E, Ogawa M, Kobayashi J, Mu A, Takata M. The ribonuclease domain function is dispensable for SLFN11 to mediate cell fate decision during replication stress response. Genes Cells 2023; 28:663-673. [PMID: 37469008 DOI: 10.1111/gtc.13056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/01/2023] [Accepted: 07/04/2023] [Indexed: 07/21/2023]
Abstract
The SLFN11 gene participates in cell fate decision following cancer chemotherapy and encodes the N-terminal ribonuclease (RNase) domain and the C-terminal helicase/ATPase domain. How these domains contribute to the chemotherapeutic response remains controversial. Here, we expressed SLFN11 containing mutations in two critical residues required for RNase activity in SLFN11-/- cells. We found that this mutant was still able to suppress DNA damage tolerance, destabilized the stalled replication forks, and perturbed recruitment of the fork protector RAD51. In contrast, we confirmed that the helicase domain was essential to accelerate fork degradation. The fork degradation by the RNase mutant was dependent on both DNA2 and MRE11 nuclease, but not on MRE11's novel interactor FXR1. Collectively, these results supported the view that the RNase domain function is dispensable for SLFN11 to mediate cell fate decision during replication stress response.
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Affiliation(s)
- Fei Qi
- Department of Interdisciplinary Environmental Sciences, Graduate School of Human and Environmental Sciences, Kyoto University, Kyoto, Japan
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Laboratory of Cancer Cell Biology, Department of Genome Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Erin Alvi
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Minori Ogawa
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Junya Kobayashi
- Department of Interdisciplinary Environmental Sciences, Graduate School of Human and Environmental Sciences, Kyoto University, Kyoto, Japan
- Laboratory of Cancer Cell Biology, Department of Genome Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Anfeng Mu
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan
| | - Minoru Takata
- Department of Interdisciplinary Environmental Sciences, Graduate School of Human and Environmental Sciences, Kyoto University, Kyoto, Japan
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Multilayer Network Research Unit, Research Coordination Alliance, Kyoto University, Kyoto, Japan
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22
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Jitobaom K, Sirihongthong T, Boonarkart C, Phakaratsakul S, Suptawiwat O, Auewarakul P. Human Schlafen 11 inhibits influenza A virus production. Virus Res 2023; 334:199162. [PMID: 37356582 PMCID: PMC10410578 DOI: 10.1016/j.virusres.2023.199162] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023]
Abstract
Schlafen (SLFN) proteins are a subset of interferon-stimulated early response genes with antiviral properties. An antiviral mechanism of SLFN11 was previously demonstrated in human immunodeficiency virus type 1 (HIV-1)-infected cells, and it was shown that SLFN11 inhibited HIV-1 virus production in a codon usage-specific manner. The codon usage patterns of many viruses are vastly different from those of their hosts. The codon usage-specific inhibition of HIV-1 expression by SLFN11 suggests that SLFN11 may be able to inhibit other viruses with a suboptimal codon usage pattern. However, the effect of SLFN11 on the replication of influenza A virus (IAV) has never been reported. The induction of SLFN11 expression was observed upon IAV infection. The reduction of SLFN11 expression also promotes influenza virus replication. Moreover, we found that overexpression of SLFN11 could reduce the expression of a reporter gene with a viral codon usage pattern, and the inhibition of viral hemagglutinin (HA) gene was codon-specific as the expression of codon optimized HA was not affected. These results indicate that SLFN11 inhibits the influenza A virus in a codon-specific manner and that SLFN11 may contribute to innate defense against influenza A viruses.
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Affiliation(s)
- Kunlakanya Jitobaom
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand
| | - Thanyaporn Sirihongthong
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand
| | - Chompunuch Boonarkart
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand
| | - Supinya Phakaratsakul
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand
| | - Ornpreya Suptawiwat
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Thailand
| | - Prasert Auewarakul
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand.
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23
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Murai J, Ceribelli M, Fu H, Redon CE, Jo U, Murai Y, Aladjem MI, Thomas CJ, Pommier Y. Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication. Mol Cancer Ther 2023; 22:985-995. [PMID: 37216280 PMCID: PMC10524552 DOI: 10.1158/1535-7163.mct-22-0552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/24/2022] [Accepted: 05/16/2023] [Indexed: 05/24/2023]
Abstract
Schlafen 11 (SLFN11) is an increasingly prominent predictive biomarker and a molecular sensor for a wide range of clinical drugs: topoisomerases, PARP and replication inhibitors, and platinum derivatives. To expand the spectrum of drugs and pathways targeting SLFN11, we ran a high-throughput screen with 1,978 mechanistically annotated, oncology-focused compounds in two isogenic pairs of SLFN11-proficient and -deficient cells (CCRF-CEM and K562). We identified 29 hit compounds that selectively kill SLFN11-proficient cells, including not only previously known DNA-targeting agents, but also the neddylation inhibitor pevonedistat (MLN-4924) and the DNA polymerase α inhibitor AHPN/CD437, which both induced SLFN11 chromatin recruitment. By inactivating cullin-ring E3 ligases, pevonedistat acts as an anticancer agent partly by inducing unscheduled re-replication through supraphysiologic accumulation of CDT1, an essential factor for replication initiation. Unlike the known DNA-targeting agents and AHPN/CD437 that recruit SLFN11 onto chromatin in 4 hours, pevonedistat recruited SLFN11 at late time points (24 hours). While pevonedistat induced unscheduled re-replication in SLFN11-deficient cells after 24 hours, the re-replication was largely blocked in SLFN11-proficient cells. The positive correlation between sensitivity to pevonedistat and SLFN11 expression was also observed in non-isogenic cancer cells in three independent cancer cell databases (NCI-60, CTRP: Cancer Therapeutics Response Portal and GDSC: Genomic of Drug Sensitivity in Cancer). The present study reveals that SLFN11 not only detects stressed replication but also inhibits unscheduled re-replication induced by pevonedistat, thereby enhancing its anticancer efficacy. It also suggests SLFN11 as a potential predictive biomarker for pevonedistat in ongoing and future clinical trials.
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Affiliation(s)
- Junko Murai
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
- Department of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon 791-0295, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
| | - Michele Ceribelli
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Haiqing Fu
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Christophe E. Redon
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Ukhyun Jo
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Yasuhisa Murai
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Mirit I. Aladjem
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Craig J. Thomas
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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24
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Hou P, Hao W, Qin B, Li M, Zhao R, Cui S. Structural and biochemical characterization of Schlafen11 N-terminal domain. Nucleic Acids Res 2023; 51:7053-7070. [PMID: 37293979 PMCID: PMC10359600 DOI: 10.1093/nar/gkad509] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/25/2023] [Accepted: 06/01/2023] [Indexed: 06/10/2023] Open
Abstract
Schlafen11 (SLFN11) is one of the most studied Schlafen proteins that plays vital roles in cancer therapy and virus-host interactions. Herein, we determined the crystal structure of the Sus scrofa SLFN11 N-terminal domain (NTD) to 2.69 Å resolution. sSLFN11-NTD is a pincer-shaped molecule that shares an overall fold with other SLFN-NTDs but exhibits distinct biochemical characteristics. sSLFN11-NTD is a potent RNase cleaving type I and II tRNAs and rRNAs, and with preference to type II tRNAs. Consistent with the codon usage-based translation suppression activity of SLFN11, sSLFN11-NTD cleaves synonymous serine and leucine tRNAs with different efficiencies in vitro. Mutational analysis revealed key determinates of sSLFN11-NTD nucleolytic activity, including the Connection-loop, active site, and key residues essential for substrate recognition, among which E42 constrains sSLFN11-NTD RNase activity, and all nonconservative mutations of E42 stimulated RNase activities. sSLFN11 inhibited the translation of proteins with a low codon adaptation index in cells, which mainly dependent on the RNase activity of the NTD because E42A enhanced the inhibitory effect, but E209A abolished inhibition. Our findings provide structural characterization of an important SLFN11 protein and expand our understanding of the Schlafen family.
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Affiliation(s)
- Pengjiao Hou
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China
- Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Beijing 100730, PR China
| | - Wei Hao
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China
- Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Beijing 100730, PR China
| | - Bo Qin
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China
- Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Beijing 100730, PR China
| | - Mengyun Li
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China
- Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Beijing 100730, PR China
| | - Rong Zhao
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China
- Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Beijing 100730, PR China
| | - Sheng Cui
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China
- Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Beijing 100730, PR China
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25
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Moliner L, Zhang B, Lamberti G, Ardizzoni A, Byers LA, Califano R. Novel therapeutic strategies for recurrent SCLC. Crit Rev Oncol Hematol 2023; 186:104017. [PMID: 37150311 DOI: 10.1016/j.critrevonc.2023.104017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/25/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023] Open
Abstract
Therapeutic options for patients with relapsed SCLC are limited, and the prognosis in this setting remains poor. While clinical outcomes for frontline treatment have modestly improved with the introduction of immunotherapy, treatment in the second-line setting persists almost unchanged. In this review, current treatment options and recent advances in molecular biology are described. Emerging therapeutic options in this setting and potential strategies to improve clinical outcomes of these patients are also addressed.
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Affiliation(s)
- Laura Moliner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Bingnan Zhang
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Giuseppe Lamberti
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, 40138, Italy
| | - Andrea Ardizzoni
- Department of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, 40138, Italy
| | - Lauren A Byers
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Raffaele Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; Division of Cancer Sciences, The University of Manchester, Manchester, M13 9NT, UK.
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26
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Huang J, Wu C, Kloeber JA, Gao H, Gao M, Zhu Q, Chang Y, Zhao F, Guo G, Luo K, Dai H, Liu S, Huang Q, Kim W, Zhou Q, Zhu S, Wu Z, Tu X, Yin P, Deng M, Wang L, Yuan J, Lou Z. SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology. Mol Cell 2023; 83:1043-1060.e10. [PMID: 36854302 PMCID: PMC10467573 DOI: 10.1016/j.molcel.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 12/23/2022] [Accepted: 02/01/2023] [Indexed: 03/02/2023]
Abstract
Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.
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Affiliation(s)
- Jinzhou Huang
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Chenming Wu
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jake A Kloeber
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA
| | - Huanyao Gao
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Ming Gao
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Qian Zhu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Yiming Chang
- Jinzhou Medical University, Shanghai East Hospital, Shanghai 200120, China
| | - Fei Zhao
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Guijie Guo
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Kuntian Luo
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Haiming Dai
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Sijia Liu
- Department of Artificial Intelligence and Informatics, Mayo Clinic, Rochester, MN 55905, USA
| | - Qiru Huang
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Wootae Kim
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Qin Zhou
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Shouhai Zhu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Zheming Wu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xinyi Tu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ping Yin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Min Deng
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Jian Yuan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200092, China.
| | - Zhenkun Lou
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
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Zhang X, Huo X, Guo H, Xue L. Combined inhibition of PARP and EZH2 for cancer treatment: Current status, opportunities, and challenges. Front Pharmacol 2022; 13:965244. [PMID: 36263120 PMCID: PMC9574044 DOI: 10.3389/fphar.2022.965244] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
Tumors with BRCA1/2 mutations or homologous recombination repair defects are sensitive to PARP inhibitors through the mechanism of synthetic lethality. Several PARP inhibitors are currently approved for ovarian, breast and pancreatic cancer in clinical practice. However, more than 40% of patients with BRCA1/2 mutations are insensitive to PARP inhibitors, which has aroused attention to the mechanism of PARP resistance and sensitization schemes. PARP inhibitor resistance is related to homologous recombination repair, stability of DNA replication forks, PARylation and epigenetic modification. Studies on epigenetics have become the hotspots of research on PARP inhibitor resistance. As an important epigenetic regulator of transcription mediated by histone methylation, EZH2 interacts with PARP through DNA homologous recombination, DNA replication, posttranslational modification, tumor immunity and other aspects. EZH2 inhibitors have been just shifting from the bench to the bedside, but the combination scheme in cancer therapy has not been fully explored yet. Recently, a revolutionary drug design combining PARP inhibitors and EZH2 inhibitors based on PROTAC techniques has shed light on the resolution of PARP inhibitor resistance. This review summarizes the interactions between EZH2 and PARP, suggests the potential PARP inhibitor sensitization effect of EZH2 inhibitors, and further discusses the potential populations that benefit from the combination of EZH2 inhibitors and PARP inhibitors.
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Affiliation(s)
- Xi Zhang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Haidian, China
| | - Xiao Huo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Haidian, China
- Biobank, Peking University Third Hospital, Haidian, China
| | - Hongyan Guo
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Haidian, China
- *Correspondence: Lixiang Xue, ; Hongyan Guo,
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Haidian, China
- Biobank, Peking University Third Hospital, Haidian, China
- *Correspondence: Lixiang Xue, ; Hongyan Guo,
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Metzner FJ, Wenzl SJ, Kugler M, Krebs S, Hopfner KP, Lammens K. Mechanistic understanding of human SLFN11. Nat Commun 2022; 13:5464. [PMID: 36115853 PMCID: PMC9482658 DOI: 10.1038/s41467-022-33123-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 09/01/2022] [Indexed: 11/12/2022] Open
Abstract
Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks. Schlafen 11 serves as an antiviral restriction factor and a predictive biomarker in cancer. Here, the authors use cryoelectron microscopy and biochemical assays to understand tRNA endoribonuclease and DNA binding functions of human Schlafen 11.
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29
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Fischietti M, Eckerdt F, Perez RE, Guillen Magaña JN, Mazewski C, Ho S, Gonzalez C, Streich LD, Beauchamp EM, Heimberger AB, Baran AH, Yue F, James CD, Platanias LC. SLFN11 Negatively Regulates Noncanonical NFκB Signaling to Promote Glioblastoma Progression. CANCER RESEARCH COMMUNICATIONS 2022; 2:966-978. [PMID: 36382088 PMCID: PMC9648417 DOI: 10.1158/2767-9764.crc-22-0192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular, and tumor biology of GBM. CRISPR/Cas9-mediated knockout of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2, and CD44. Loss of SLFN11 stimulated expression of NFκB target genes, consistent with a negative regulatory role for SLFN11 on the NFκB pathway. Furthermore, our studies identify p21 as a direct transcriptional target of NFκB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.
Significance:
We identify a negative regulatory role for SLFN11 in noncanonical NFκB signaling that results in suppression of the cell-cycle inhibitor p21. We provide evidence that SLFN11 contributes to regulation of stem cell markers in GBM, promoting the malignant phenotype. In addition, SLFN11 targeting triggers p21 expression and antitumor responses. Our studies define a highly novel function for SLFN11 and identify it as a potential therapeutic target for GBM.
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Affiliation(s)
- Mariafausta Fischietti
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Frank Eckerdt
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- 3Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Ricardo E. Perez
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | | | - Candice Mazewski
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Sang Ho
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
| | - Christopher Gonzalez
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
| | - Lukas D. Streich
- 4Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Elspeth M. Beauchamp
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- 5Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Amy B. Heimberger
- 3Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Aneta H. Baran
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- 5Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Feng Yue
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 6Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - C. David James
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 3Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Leonidas C. Platanias
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- 2Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- 5Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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30
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PARP inhibitors in small cell lung cancer: The underlying mechanisms and clinical implications. Biomed Pharmacother 2022; 153:113458. [DOI: 10.1016/j.biopha.2022.113458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 11/18/2022] Open
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Xiong J, Barayan R, Louie AV, Lok BH. Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review. Semin Cancer Biol 2022; 86:521-542. [PMID: 35917883 DOI: 10.1016/j.semcancer.2022.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/02/2022] [Accepted: 07/29/2022] [Indexed: 10/31/2022]
Abstract
Small cell lung cancer (SCLC) is treated as a monolithic disease despite the evident intra- and intertumoral heterogeneity. Non-specific DNA-damaging agents have remained the first-line treatment for decades. Recently, emerging transcriptomic and genomic profiling of SCLC tumors identified distinct SCLC subtypes and vulnerabilities towards targeted therapeutics, including inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARPi). SCLC cell lines and tumors exhibited an elevated level of PARP1 protein and mRNA compared to healthy lung tissues and other subtypes of lung tumors. Notable responses to PARPi were also observed in preclinical SCLC models. Clinically, PARPi monotherapy exerted variable benefits for SCLC patients. To date, research is being vigorously conducted to examine predictive biomarkers of PARPi response and various PARPi combination strategies to maximize the clinical utility of PARPi. This narrative review summarizes existing preclinical evidence supporting PARPi monotherapy, combination therapy, and respective translation to the clinic. Specifically, we covered the combination of PARPi with DNA-damaging chemotherapy (cisplatin, etoposide, temozolomide), thoracic radiotherapy, immunotherapy (immune checkpoint inhibitors), and many other novel therapeutic agents that target DNA damage response, tumor microenvironment, epigenetic modulation, angiogenesis, the ubiquitin-proteasome system, or autophagy. Putative biomarkers, such as SLFN11 expression, MGMT methylation, E2F1 expression, and platinum sensitivity, which may be predictive of response to distinct therapeutic combinations, were also discussed. The future of SCLC treatment is undergoing rapid change with a focus on tailored and personalized treatment strategies. Further development of cancer therapy with PARPi will immensely benefit at least a subset of biomarker-defined SCLC patients.
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Affiliation(s)
- Jiaqi Xiong
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Ranya Barayan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Alexander V Louie
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Odette Cancer Centre - Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
| | - Benjamin H Lok
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
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Structural, molecular, and functional insights into Schlafen proteins. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:730-738. [PMID: 35768579 PMCID: PMC9256597 DOI: 10.1038/s12276-022-00794-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/08/2022] [Accepted: 04/14/2022] [Indexed: 11/30/2022]
Abstract
Schlafen (SLFN) genes belong to a vertebrate gene family encoding proteins with high sequence homology. However, each SLFN is functionally divergent and differentially expressed in various tissues and species, showing a wide range of expression in cancer and normal cells. SLFNs are involved in various cellular and tissue-specific processes, including DNA replication, proliferation, immune and interferon responses, viral infections, and sensitivity to DNA-targeted anticancer agents. The fundamental molecular characteristics of SLFNs and their structures are beginning to be elucidated. Here, we review recent structural insights into the N-terminal, middle and C-terminal domains (N-, M-, and C-domains, respectively) of human SLFNs and discuss the current understanding of their biological roles. We review the distinct molecular activities of SLFN11, SLFN5, and SLFN12 and the relevance of SLFN11 as a predictive biomarker in oncology. The diverse roles that Schlafen family proteins play in cell proliferation, immune modulation, and other biological processes make them promising targets for treating and tracking diseases, especially cancer. Ukhyun Jo and Yves Pommier from the National Cancer Institute in Bethesda, USA, review the molecular characteristics and structural features of Schlafen proteins. These proteins take their name from the German word for “sleep”, as the first described Schlafen proteins caused cells to stop dividing, although later reports found that related members of the same protein family serve myriad cellular functions, including in the regulation of DNA replication. A better understanding of Schlafen proteins could open up new avenues in cancer management, for instance, diagnostics that monitor activity levels of one such protein, SLFN11, could help oncologists predict how well patients might respond to anti-cancer therapies.
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Abbotts R, Dellomo AJ, Rassool FV. Pharmacologic Induction of BRCAness in BRCA-Proficient Cancers: Expanding PARP Inhibitor Use. Cancers (Basel) 2022; 14:2640. [PMID: 35681619 PMCID: PMC9179544 DOI: 10.3390/cancers14112640] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 12/17/2022] Open
Abstract
The poly(ADP-ribose) polymerase (PARP) family of proteins has been implicated in numerous cellular processes, including DNA repair, translation, transcription, telomere maintenance, and chromatin remodeling. Best characterized is PARP1, which plays a central role in the repair of single strand DNA damage, thus prompting the development of small molecule PARP inhibitors (PARPi) with the intent of potentiating the genotoxic effects of DNA damaging agents such as chemo- and radiotherapy. However, preclinical studies rapidly uncovered tumor-specific cytotoxicity of PARPi in a subset of cancers carrying mutations in the BReast CAncer 1 and 2 genes (BRCA1/2), which are defective in the homologous recombination (HR) DNA repair pathway, and several PARPi are now FDA-approved for single agent treatment in BRCA-mutated tumors. This phenomenon, termed synthetic lethality, has now been demonstrated in tumors harboring a number of repair gene mutations that produce a BRCA-like impairment of HR (also known as a 'BRCAness' phenotype). However, BRCA mutations or BRCAness is present in only a small subset of cancers, limiting PARPi therapeutic utility. Fortunately, it is now increasingly recognized that many small molecule agents, targeting a variety of molecular pathways, can induce therapeutic BRCAness as a downstream effect of activity. This review will discuss the potential for targeting a broad range of molecular pathways to therapeutically induce BRCAness and PARPi synthetic lethality.
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Affiliation(s)
- Rachel Abbotts
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.J.D.); (F.V.R.)
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Anna J. Dellomo
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.J.D.); (F.V.R.)
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Feyruz V. Rassool
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.J.D.); (F.V.R.)
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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A PARylation-phosphorylation cascade promotes TOPBP1 loading and RPA-RAD51 exchange in homologous recombination. Mol Cell 2022; 82:2571-2587.e9. [PMID: 35597237 DOI: 10.1016/j.molcel.2022.04.031] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 02/14/2022] [Accepted: 04/22/2022] [Indexed: 01/30/2023]
Abstract
The efficiency of homologous recombination (HR) in the repair of DNA double-strand breaks (DSBs) is closely associated with genome stability and tumor response to chemotherapy. While many factors have been functionally characterized in HR, such as TOPBP1, their precise regulation remains unclear. Here, we report that TOPBP1 interacts with the RNA-binding protein HTATSF1 in a cell-cycle- and phosphorylation-dependent manner. Mechanistically, CK2 phosphorylates HTATSF1 to facilitate binding to TOPBP1, which promotes S-phase-specific TOPBP1 recruitment to damaged chromatin and subsequent RPA/RAD51-dependent HR, genome integrity, and cancer-cell viability. The localization of HTATSF1-TOPBP1 to DSBs is potentially independent of the transcription-coupled RNA-binding and processing capacity of HTATSF1 but rather relies on the recognition of poly(ADP-ribosyl)ated RPA by HTATSF1, which can be blunted with PARP inhibitors. Together, our study provides a mechanistic insight into TOPBP1 loading at HR-prone DSB sites via HTATSF1 and reveals how RPA-RAD51 exchange is tuned by a PARylation-phosphorylation cascade.
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35
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Can Schlafen 11 Help to Stratify Ovarian Cancer Patients Treated with DNA-Damaging Agents? Cancers (Basel) 2022; 14:cancers14102353. [PMID: 35625957 PMCID: PMC9139752 DOI: 10.3390/cancers14102353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/25/2022] [Accepted: 05/06/2022] [Indexed: 02/04/2023] Open
Abstract
Platinum-based chemotherapy has been the cornerstone of systemic treatment in ovarian cancer. Since no validated molecular predictive markers have been identified yet, the response to platinum-based chemotherapy has been evaluated clinically, based on platinum-free interval. The new promising marker Schlafen 11 seems to correlate with sensitivity or resistance to DNA-damaging agents, including platinum compounds or PARP inhibitors in various types of cancer. We provide background information about the function of Schlafen 11, its evaluation in tumor tissue, and its prevalence in ovarian cancer. We discuss the current evidence of the correlation of Schlafen 11 expression in ovarian cancer with treatment outcomes and the potential use of Schlafen 11 as the key predictive and prognostic marker that could help to better stratify ovarian cancer patients treated with platinum-based chemotherapy or PARP inhibitors. We also provide perspectives on future directions in the research on this promising marker.
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Majeed S, Aparnathi MK, Nixon KC, Venkatasubramanian V, Rahman F, Song L, Weiss J, Barayan R, Sugumar V, Barghout SH, Pearson JD, Bremner R, Schimmer AD, Tsao MS, Liu G, Lok BH. Targeting the Ubiquitin-Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer. Clin Cancer Res 2022; 28:1966-1978. [PMID: 35165102 PMCID: PMC9365348 DOI: 10.1158/1078-0432.ccr-21-0344] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 10/29/2021] [Accepted: 02/09/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeutic target for SCLC. We preclinically evaluated TAK-243, a first-in-class small molecule E1 inhibitor against UBA1. EXPERIMENTAL DESIGN We assessed TAK-243 in 26 SCLC cell-lines as monotherapy and combined with C/E, the PARP-inhibitor, olaparib, and with radiation using cell viability assays. We interrogated TAK-243 response with gene expression to identify candidate biomarkers. We evaluated TAK-243 alone and in combination with olaparib or radiotherapy with SCLC patient-derived xenografts (PDX). RESULTS Most SCLC cell lines were sensitive to TAK-243 monotherapy (EC50 median 15.8 nmol/L; range 10.2 nmol/L-367.3 nmol/L). TAK-243 sensitivity was associated with gene-sets involving the cell cycle, DNA and chromatin organization, and DNA damage repair, while resistance associated with cellular respiration, translation, and neurodevelopment. These associations were also observed in SCLC PDXs. TAK-243 synergized with C/E and olaparib in vitro across sensitive and resistant SCLC cell lines. Considerable TAK-243-olaparib synergy was observed in an SCLC PDX resistant to both drugs individually. TAK-243 radiosensitization was also observed in an SCLC PDX. CONCLUSIONS TAK-243 displays efficacy in SCLC preclinical models. Enrichment of gene sets is associated with TAK-243 sensitivity and resistance. TAK-243 exhibits synergy when combined with genotoxic therapies in cell lines and PDXs. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes, both as a single agent and in combination with existing therapies.
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Affiliation(s)
- Safa Majeed
- University of Toronto, Toronto, Ontario, Canada
| | - Mansi K. Aparnathi
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Kevin C.J. Nixon
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | - Fariha Rahman
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Lifang Song
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Jessica Weiss
- Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | - Vijithan Sugumar
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Samir H. Barghout
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Joel D. Pearson
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
| | - Rod Bremner
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
| | - Aaron D. Schimmer
- University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ming S. Tsao
- University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Geoffrey Liu
- University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Benjamin H. Lok
- University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Schlafens Can Put Viruses to Sleep. Viruses 2022; 14:v14020442. [PMID: 35216035 PMCID: PMC8875196 DOI: 10.3390/v14020442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 12/21/2022] Open
Abstract
The Schlafen gene family encodes for proteins involved in various biological tasks, including cell proliferation, differentiation, and T cell development. Schlafens were initially discovered in mice, and have been studied in the context of cancer biology, as well as their role in protecting cells during viral infection. This protein family provides antiviral barriers via direct and indirect effects on virus infection. Schlafens can inhibit the replication of viruses with both RNA and DNA genomes. In this review, we summarize the cellular functions and the emerging relationship between Schlafens and innate immunity. We also discuss the functions and distinctions of this emerging family of proteins as host restriction factors against viral infection. Further research into Schlafen protein function will provide insight into their mechanisms that contribute to intrinsic and innate host immunity.
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Prisciandaro M, Antista M, Raimondi A, Corti F, Morano F, Centonze G, Sabella G, Mangogna A, Randon G, Pagani F, Prinzi N, Niger M, Corallo S, Castiglioni di Caronno E, Massafra M, Bartolomeo MD, de Braud F, Milione M, Pusceddu S. Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective. Front Oncol 2022; 12:780716. [PMID: 35186729 PMCID: PMC8856722 DOI: 10.3389/fonc.2022.780716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/10/2022] [Indexed: 11/26/2022] Open
Abstract
Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
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Affiliation(s)
- Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- *Correspondence: Michele Prisciandaro,
| | - Maria Antista
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Corti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Sabella
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
| | - Giovanni Randon
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pagani
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Marco Massafra
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Massimo Milione
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Poly(ADP-Ribose) Polymerase Inhibition in Small Cell Lung Cancer: A Review. Cancer J 2021; 27:476-481. [PMID: 34904810 DOI: 10.1097/ppo.0000000000000555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with high and rapid relapse rates and poor outcomes. Treatment for SCLC has historically been limited by the lack of targetable driver genomic lesions, however recent developments in the underpinnings of genomic instability in SCLC and understanding of its transcriptional subtypes have led to increased interest in the use of poly(ADP-ribose) polymerase (PARP) inhibitors as a rationale therapy. Poly(ADP-ribose) polymerase inhibitors, historically designed to target BRCA1/2-mutated malignancies, capitalize on synthetic lethality in homologous recombination-deficient tumors. In this review, we outline the mechanistic rationale for the use of PARP inhibitors in treating SCLC and detail key clinical trials investigating their use in combination with chemotherapy and immunotherapy. We describe developments in the understanding of biomarkers for sensitivity to therapy and highlight further investigational directions for the use of PARP inhibitors in treating SCLC.
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40
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Sen A, Prager BC, Zhong C, Park D, Zhu Z, Gimple RC, Wu Q, Bernatchez JA, Beck S, Clark AE, Siqueira-Neto JL, Rich JN, McVicker G. Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma. Cancer Res 2021; 82:377-390. [PMID: 34903607 DOI: 10.1158/0008-5472.can-21-0810] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 09/13/2021] [Accepted: 12/02/2021] [Indexed: 11/16/2022]
Abstract
Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. To investigate recurrently dysregulated genes in glioblastoma we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients. A total of 118 genes were found with recurrent ASE preferentially in GSCs compared to normal tissues. These genes were enriched for apoptotic regulators, including schlafen family member 11 (SLFN11). Loss of SLFN11 gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and PARP inhibition. Conversely, low SLFN11 expression rendered GSCs susceptible to the oncolytic flavivirus Zika. This discovery effort based upon ASE revealed novel points of vulnerability in GSCs, suggesting a potential alternative treatment strategy for chemotherapy resistant glioblastoma.
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Affiliation(s)
- Arko Sen
- Salk Institute for Biological Studies
| | - Briana C Prager
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic
| | | | | | - Zhe Zhu
- Medicine, University of California, San Diego
| | | | - Qiulian Wu
- Medicine, University of California - San Diego School of Medicine
| | - Jean A Bernatchez
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego
| | | | | | | | - Jeremy N Rich
- Department of Neurology, University of Pittsburgh Cancer Institute
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Yin YP, Ma LY, Cao GZ, Hua JH, Lv XT, Lin WC. FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11. Acta Pharmacol Sin 2021; 43:2119-2127. [PMID: 34893686 PMCID: PMC9343610 DOI: 10.1038/s41401-021-00817-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 11/06/2021] [Indexed: 11/09/2022]
Abstract
The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.
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Taniyama D, Sakamoto N, Takashima T, Takeda M, Pham QT, Ukai S, Maruyama R, Harada K, Babasaki T, Sekino Y, Hayashi T, Sentani K, Pommier Y, Murai J, Yasui W. Prognostic impact of Schlafen 11 in bladder cancer patients treated with platinum-based chemotherapy. Cancer Sci 2021; 113:784-795. [PMID: 34808009 PMCID: PMC8819307 DOI: 10.1111/cas.15207] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/28/2021] [Accepted: 11/04/2021] [Indexed: 12/15/2022] Open
Abstract
The utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum‐based chemotherapy has been established for cancers from different histologies. However, the therapeutic relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum‐based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum‐based chemotherapy, the SLFN11‐positive group (n = 25) showed significantly better overall survival than the SLFN11‐negative group (n = 25, P = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11‐0.91; P = .033). Conversely, in the cohort of 70 BC cases not receiving platinum‐based chemotherapy, the SLFN11‐positive group (n = 29) showed significantly worse overall survival than the SLFN11‐negative group (n = 41, P = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5‐azacytidine and entinostat restored SLFN11 expression and resensitized cells to cisplatin and carboplatin in SLFN11‐negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum‐based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression.
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Affiliation(s)
- Daiki Taniyama
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tsuyoshi Takashima
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Masahiko Takeda
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Quoc Thang Pham
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shoichi Ukai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryota Maruyama
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenji Harada
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Babasaki
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yohei Sekino
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tetsutaro Hayashi
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Junko Murai
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers. Br J Cancer 2021; 125:1333-1340. [PMID: 34294893 PMCID: PMC8576031 DOI: 10.1038/s41416-021-01476-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/25/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.
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44
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Murai Y, Jo U, Murai J, Fukuda S, Takebe N, Pommier Y. Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway. iScience 2021; 24:103173. [PMID: 34693224 PMCID: PMC8517841 DOI: 10.1016/j.isci.2021.103173] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/16/2021] [Accepted: 09/22/2021] [Indexed: 12/28/2022] Open
Abstract
Schlafen11 (SLFN11) is referred to as interferon (IFN)-inducible. Based on cancer genomic databases, we identified human acute myeloid and lymphoblastic leukemia cells with gain-of-function mutations in the Janus kinase (JAK) family as exhibiting high SLFN11 expression. In these cells, the clinical JAK inhibitors cerdulatinib, ruxolitinib, and tofacitinib reduced SLFN11 expression, but IFN did not further induce SLFN11 despite phosphorylated STAT1. We provide evidence that suppression of SLFN11 by JAK inhibitors is caused by inactivation of the non-canonical IFN pathway controlled by AKT and ERK. Accordingly, the AKT and ERK inhibitors MK-2206 and SCH77284 suppressed SLFN11 expression. Both also suppressed the E26 transformation-specific (ETS)-family genes ETS-1 and FLI-1 that act as transcription factors for SLFN11. Moreover, SLFN11 expression was inhibited by the ETS inhibitor TK216. Our study reveals that SLFN11 expression is regulated via the JAK, AKT and ERK, and ETS axis. Pharmacological suppression of SLFN11 warrants future studies.
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Affiliation(s)
- Yasuhisa Murai
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Ukhyun Jo
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Junko Murai
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Naoko Takebe
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Developmental Therapeutics Branch and Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
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45
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Jo U, Murai Y, Takebe N, Thomas A, Pommier Y. Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11. Cancers (Basel) 2021; 13:4601. [PMID: 34572827 PMCID: PMC8465591 DOI: 10.3390/cancers13184601] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022] Open
Abstract
Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.
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Affiliation(s)
- Ukhyun Jo
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4264, USA; (Y.M.); (A.T.)
| | - Yasuhisa Murai
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4264, USA; (Y.M.); (A.T.)
- Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Naoko Takebe
- Developmental Therapeutics Branch and Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD 20892-4264, USA;
| | - Anish Thomas
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4264, USA; (Y.M.); (A.T.)
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4264, USA; (Y.M.); (A.T.)
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46
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Al-Marsoummi S, Vomhof-DeKrey EE, Basson MD. Schlafens: Emerging Proteins in Cancer Cell Biology. Cells 2021; 10:2238. [PMID: 34571887 PMCID: PMC8465726 DOI: 10.3390/cells10092238] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/29/2022] Open
Abstract
Schlafens (SLFN) are a family of genes widely expressed in mammals, including humans and rodents. These intriguing proteins play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication. The emerging evidence is implicating Schlafens in cancer biology and chemosensitivity. Although Schlafens share common domains and a high degree of homology, different Schlafens act differently. In particular, they show specific and occasionally opposing effects in some cancer types. This review will briefly summarize the history, structure, and non-malignant biological functions of Schlafens. The roles of human and mouse Schlafens in different cancer types will then be outlined. Finally, we will discuss the implication of Schlafens in the anti-tumor effect of interferons and the use of Schlafens as predictors of chemosensitivity.
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Affiliation(s)
- Sarmad Al-Marsoummi
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (E.E.V.-D.)
| | - Emilie E. Vomhof-DeKrey
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (E.E.V.-D.)
- Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
| | - Marc D. Basson
- Department of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (S.A.-M.); (E.E.V.-D.)
- Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
- Department of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
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47
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Gartrell J, Mellado-Largarde M, Clay MR, Bahrami A, Sahr NA, Sykes A, Blankenship K, Hoffmann L, Xie J, Cho HP, Twarog N, Connelly M, Yan KK, Yu J, Porter SN, Pruett-Miller SM, Neale G, Tinkle CL, Federico SM, Stewart EA, Shelat AA. SLFN11 is Widely Expressed in Pediatric Sarcoma and Induces Variable Sensitization to Replicative Stress Caused By DNA-Damaging Agents. Mol Cancer Ther 2021; 20:2151-2165. [PMID: 34413129 DOI: 10.1158/1535-7163.mct-21-0089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 08/09/2021] [Indexed: 01/02/2023]
Abstract
Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA-damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress and has been implicated as a potential biomarker to predict sensitivity to DNA-damaging agents (DDA). SLFN11 expression was quantified in 220 children with solid tumors using IHC. Sensitivity to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN) was assessed in sarcoma cell lines, including SLFN11 knock-out (KO) and overexpression models, and a patient-derived orthotopic xenograft model (PDOX). SLFN11 was expressed in 69% of pediatric sarcoma sampled, including 90% and 100% of Ewing sarcoma and desmoplastic small round-cell tumors, respectively, although the magnitude of expression varied widely. In sarcoma cell lines, protein expression strongly correlated with response to TAL and IRN, with SLFN11 KO resulting in significant loss of sensitivity in vitro and in vivo Surprisingly, retrospective analysis of children with sarcoma found no association between SLFN11 levels and favorable outcome. Subsequently, high SLFN11 expression was confirmed in a PDOX model derived from a patient with recurrent Ewing sarcoma who failed to respond to treatment with TAL + IRN. Selective inhibition of BCL-xL increased sensitivity to TAL + IRN in SLFN11-positive resistant tumor cells. Although SLFN11 appears to drive sensitivity to replicative stress in pediatric sarcomas, its potential to act as a biomarker may be limited to certain tumor backgrounds or contexts. Impaired apoptotic response may be one mechanism of resistance to DDA-induced replicative stress.
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Affiliation(s)
- Jessica Gartrell
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Marcia Mellado-Largarde
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Michael R Clay
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Armita Bahrami
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Natasha A Sahr
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - April Sykes
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Kaley Blankenship
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Lauren Hoffmann
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Jia Xie
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Hyekyung P Cho
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Nathaniel Twarog
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Michele Connelly
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Koon-Kiu Yan
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Jiyang Yu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Shaina N Porter
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
- The Center for Advanced Genomic Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Shondra M Pruett-Miller
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
- The Center for Advanced Genomic Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Geoffrey Neale
- Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Christopher L Tinkle
- Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Sara M Federico
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Elizabeth A Stewart
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Anang A Shelat
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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48
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Li X, Li C, Guo C, Zhao Q, Cao J, Huang HY, Yue M, Xue Y, Jin Y, Hu L, Ji H. PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer. J Genet Genomics 2021; 48:640-651. [PMID: 34167917 DOI: 10.1016/j.jgg.2021.04.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/02/2021] [Accepted: 04/02/2021] [Indexed: 12/24/2022]
Abstract
Small cell lung cancer (SCLC) is a phenotypically heterogeneous disease with an extremely poor prognosis, which is mainly attributed to the rapid development of resistance to chemotherapy. However, the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear. Through comprehensive bioinformatic analyses, we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy. Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant. Mechanistically, activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance. Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors. Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance, which holds important clinical implications for improving SCLC treatment.
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Affiliation(s)
- Xuefeng Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; Department of Medical Oncology, The First Affiliated Hospita, Hengyang MedicalSchool, University of South China, Hengyang, Hunan 421001, China
| | - Cheng Li
- Department of Medical Oncology, The First Affiliated Hospita, Hengyang MedicalSchool, University of South China, Hengyang, Hunan 421001, China
| | - Chenchen Guo
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qiqi Zhao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China
| | - Jiayu Cao
- University of Chinese Academy of Sciences, Beijing 100049, China; CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Hsin-Yi Huang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Meiting Yue
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yun Xue
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yujuan Jin
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Liang Hu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Hongbin Ji
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
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49
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Takashima T, Taniyama D, Sakamoto N, Yasumoto M, Asai R, Hattori T, Honma R, Thang PQ, Ukai S, Maruyama R, Harada K, Kuraoka K, Tanabe K, Sasaki AT, Ohdan H, Morii E, Murai J, Yasui W. Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers. Br J Cancer 2021; 125:65-77. [PMID: 33785877 PMCID: PMC8257722 DOI: 10.1038/s41416-021-01364-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC. METHODS We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids. RESULTS GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs. CONCLUSIONS This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.
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Affiliation(s)
- Tsuyoshi Takashima
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Daiki Taniyama
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Maika Yasumoto
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryuichi Asai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takuya Hattori
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ririno Honma
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Pham Quoc Thang
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shoichi Ukai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryota Maruyama
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenji Harada
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuya Kuraoka
- Institute for Clinical Research, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
- Department of Diagnostic Pathology, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Kazuaki Tanabe
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsuo T Sasaki
- Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eiichi Morii
- Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Junko Murai
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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50
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Coussy F, El-Botty R, Château-Joubert S, Dahmani A, Montaudon E, Leboucher S, Morisset L, Painsec P, Sourd L, Huguet L, Nemati F, Servely JL, Larcher T, Vacher S, Briaux A, Reyes C, La Rosa P, Lucotte G, Popova T, Foidart P, Sounni NE, Noel A, Decaudin D, Fuhrmann L, Salomon A, Reyal F, Mueller C, Ter Brugge P, Jonkers J, Poupon MF, Stern MH, Bièche I, Pommier Y, Marangoni E. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci Transl Med 2021; 12:12/531/eaax2625. [PMID: 32075943 DOI: 10.1126/scitranslmed.aax2625] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 10/17/2019] [Accepted: 01/16/2020] [Indexed: 12/16/2022]
Abstract
Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.
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Affiliation(s)
- Florence Coussy
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France.,Medical Oncology Department, Institut Curie, PSL Research University, 75005 Paris, France.,Genetics Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Rania El-Botty
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | | | - Ahmed Dahmani
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Elodie Montaudon
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Sophie Leboucher
- Institut Curie, PSL Research University, UMR3306, 91405 Orsay, France
| | - Ludivine Morisset
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Pierre Painsec
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Laura Sourd
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Léa Huguet
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Fariba Nemati
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Jean-Luc Servely
- BioPôle Alfort, Ecole Nationale Vétérinaire d'Alfort, 94704 Maisons Alfort, France.,INRA, PHASE Department, 37380 Nouzilly, France
| | | | - Sophie Vacher
- Genetics Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Adrien Briaux
- Genetics Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Cécile Reyes
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Philippe La Rosa
- INSERM, U900, 75005 Paris, France.,Institut Curie, PSL Research University, 75005 Paris, France
| | - Georges Lucotte
- INSERM, U900, 75005 Paris, France.,Institut Curie, PSL Research University, 75005 Paris, France
| | - Tatiana Popova
- Institut Curie, PSL Research University, 75005 Paris, France.,INSERM U830, 75005 Paris, France
| | - Pierre Foidart
- Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium
| | - Nor Eddine Sounni
- Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium
| | - Agnès Noel
- Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), University of Liège, Liège 4000, Belgium
| | - Didier Decaudin
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France.,Medical Oncology Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Laetitia Fuhrmann
- Department of Pathology, Institut Curie, PSL Research University, 75005 Paris, France
| | - Anne Salomon
- Department of Pathology, Institut Curie, PSL Research University, 75005 Paris, France
| | - Fabien Reyal
- Surgery Department, Institut Curie, PSL Research University, 75005 Paris, France.,U932, Immunity and Cancer, INSERM, Institut Curie, 75005 Paris, France
| | - Christopher Mueller
- Queen's Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Petra Ter Brugge
- Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Amsterdam, 1066 CX, Netherlands
| | - Jos Jonkers
- Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Amsterdam, 1066 CX, Netherlands
| | - Marie-France Poupon
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Marc-Henri Stern
- Institut Curie, PSL Research University, 75005 Paris, France.,INSERM U830, 75005 Paris, France
| | - Ivan Bièche
- Genetics Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Elisabetta Marangoni
- Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France.
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