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1
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Horak J, Vallusova D, Cumova A, Holy P, Vodicka P, Opattova A. Inhibition of homologous recombination repair by Mirin in ovarian cancer ameliorates carboplatin therapy response in vitro. Mutagenesis 2025; 40:87-95. [PMID: 38099488 DOI: 10.1093/mutage/gead036] [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: 09/11/2023] [Accepted: 12/13/2023] [Indexed: 03/18/2025] Open
Abstract
Chemoresistance poses one of the most significant challenges of cancer therapy. Carboplatin (CbPt) is one of the most used chemotherapeutics in ovarian cancer (OVC) treatment. MRE11 constitutes a part of homologous recombination (HR), which is responsible for the repair of CbPt-induced DNA damage, particularly DNA crosslinks. The study's main aim was to address the role of HR in CbPt chemoresistance in OVC and to evaluate the possibility of overcoming CbPt chemoresistance by Mirin-mediated MRE11 inhibition in an OVC cell line. Lower expression of MRE11 was associated with better overall survival in a cohort of OVC patients treated with platinum drugs (TCGA dataset, P < 0.05). Using in vitro analyses, we showed that the high expression of HR genes drives the CbPt chemoresistance in our CbPt-resistant cell line model. Moreover, the HR inhibition by Mirin not only increased sensitivity to carboplatin (P < 0.05) but also rescued the sensitivity in the CbPt-resistant model (P < 0.05). Our results suggest that MRE11 inhibition with Mirin may represent a promising way to overcome OVC resistance. More therapy options will ultimately lead to better personalized cancer therapy and improvement of patients' survival.
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Affiliation(s)
- Josef Horak
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine Czech Academy of Sciences (CAS), 142 20 Prague, Czech Republic
- Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
| | | | - Andrea Cumova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine Czech Academy of Sciences (CAS), 142 20 Prague, Czech Republic
- First Faculty of Medicine, Charles University, 121 08 Prague, Czech Republic
| | - Petr Holy
- Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
- Toxicogenomics Unit, National Institute of Public Health, 100 00 Prague, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine Czech Academy of Sciences (CAS), 142 20 Prague, Czech Republic
- First Faculty of Medicine, Charles University, 121 08 Prague, Czech Republic
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
| | - Alena Opattova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine Czech Academy of Sciences (CAS), 142 20 Prague, Czech Republic
- First Faculty of Medicine, Charles University, 121 08 Prague, Czech Republic
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
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Liu Z, Jiang H, Lee SY, Kong N, Chan YW. FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition. Cell Rep 2024; 43:114464. [PMID: 38985669 DOI: 10.1016/j.celrep.2024.114464] [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: 12/19/2023] [Revised: 05/22/2024] [Accepted: 06/24/2024] [Indexed: 07/12/2024] Open
Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPis) exhibit remarkable anticancer activity in tumors with homologous recombination (HR) gene mutations. However, the role of other DNA repair proteins in PARPi-induced lethality remains elusive. Here, we reveal that FANCM promotes PARPi resistance independent of the core Fanconi anemia (FA) complex. FANCM-depleted cells retain HR proficiency, acting independently of BRCA1 in response to PARPis. FANCM depletion leads to increased DNA damage in the second S phase after PARPi exposure, driven by elevated single-strand DNA (ssDNA) gap formation behind replication forks in the first S phase. These gaps arise from both 53BP1- and primase and DNA directed polymerase (PRIMPOL)-dependent mechanisms. Notably, FANCM-depleted cells also exhibit reduced resection of collapsed forks, while 53BP1 deletion restores resection and mitigates PARPi sensitivity. Our results suggest that FANCM counteracts 53BP1 to repair PARPi-induced DNA damage. Furthermore, FANCM depletion leads to increased chromatin bridges and micronuclei formation after PARPi treatment, elucidating the mechanism underlying extensive cell death in FANCM-depleted cells.
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Affiliation(s)
- Zeyuan Liu
- School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Huadong Jiang
- School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Sze Yuen Lee
- School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Nannan Kong
- School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Ying Wai Chan
- School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
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Jin Y, Wang L, Jin C, Zhang N, Shimizu S, Xiao W, Guo C, Liu X, Si H. A Novel Inhibitor of Poly( ADP- Ribose) Polymerase-1 Inhibits Proliferation of a BRCA-Deficient Breast Cancer Cell Line via the DNA Damage- Activated cGAS-STING Pathway. Chem Res Toxicol 2024; 37:561-570. [PMID: 38534178 DOI: 10.1021/acs.chemrestox.3c00343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Loss-of-function mutations in the Breast Cancer Susceptibility Gene (BRCA1 and BRCA2) are often detected in patients with breast cancer. Poly(ADP-ribose) polymerase-1 (PARP1) plays a key role in the repair of DNA strand breaks, and PARP inhibitors have been shown to induce highly selective killing of BRCA1/2-deficient tumor cells, a mechanism termed synthetic lethality. In our previous study, a novel PARP1 inhibitor─(E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)-N-(4-fluorophenyl) hydrazine-1-carbothioamide (4F-DDC)─was synthesized, which significantly inhibited PARP1 activity with an IC50 value of 82 ± 9 nM. The current study aimed to explore the mechanism(s) underlying the antitumor activity of 4F-DDC under in vivo and in vitro conditions. 4F-DDC was found to selectively inhibit the proliferation of BRCA mutant cells, with highly potent effects on HCC-1937 (BRCA1-/-) cells. Furthermore, 4F-DDC was found to induce apoptosis and G2/M cell cycle arrest in HCC-1937 cells. Interestingly, immunofluorescence and Western blot results showed that 4F-DDC induced DNA double strand breaks and further activated the cGAS-STING pathway in HCC-1937 cells. In vivo analysis results revealed that 4F-DDC inhibited the growth of HCC-1937-derived tumor xenografts, possibly via the induction of DNA damage and activation of the cGAS-STING pathway. In summary, the current study provides a new perspective on the antitumor mechanism of PARP inhibitors and showcases the therapeutic potential of 4F-DDC in the treatment of breast cancer.
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Affiliation(s)
- Yonglong Jin
- Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Lijie Wang
- Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Chengxue Jin
- Department of Molecular Craniofacial Embryology and Oral Histology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Oral, Plastic and Aesthetic Surgery, Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China
| | - Na Zhang
- Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Shosei Shimizu
- Department of Radiotherapy, Yizhou Tumor Hospital, Zhuozhou 072750, China
- Department of Radiotherapy, University of Tsukuba Hospital, Tsukuba 305-8576, Japan
| | - Wenjing Xiao
- Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Chuanlong Guo
- Department of Pharmacy, Qingdao University of Science and Technology, Qingdao 266041, China
| | - Xiguang Liu
- Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Hongzong Si
- School of Public Health, Qingdao University, Qingdao 266071, China
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Zaman N, Kushwah AS, Badriprasad A, Chakraborty G. Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:257-301. [PMID: 39396849 PMCID: PMC11855062 DOI: 10.1016/bs.ircmb.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.
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Affiliation(s)
- Nabila Zaman
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Atar Singh Kushwah
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Anagha Badriprasad
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Goutam Chakraborty
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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Collet L, Hanvic B, Turinetto M, Treilleux I, Chopin N, Le Saux O, Ray-Coquard I. BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges. Front Oncol 2024; 14:1354427. [PMID: 38544832 PMCID: PMC10965616 DOI: 10.3389/fonc.2024.1354427] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/12/2024] [Indexed: 11/11/2024] Open
Abstract
BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.
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Affiliation(s)
- Laetitia Collet
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
- Medical Oncology Department, Centre Léon Bérard, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
| | - Brunhilde Hanvic
- Medical Oncology Department, Centre Léon Bérard, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
| | | | | | | | - Olivia Le Saux
- Medical Oncology Department, Centre Léon Bérard, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
| | - Isabelle Ray-Coquard
- Medical Oncology Department, Centre Léon Bérard, Lyon, France
- University Claude Bernard Lyon 1, Lyon, France
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Pantaleo A, Forte G, Fasano C, Lepore Signorile M, Sanese P, De Marco K, Di Nicola E, Latrofa M, Grossi V, Disciglio V, Simone C. Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review. Cancers (Basel) 2023; 16:56. [PMID: 38201484 PMCID: PMC10778202 DOI: 10.3390/cancers16010056] [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: 11/09/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance.
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Affiliation(s)
- Antonino Pantaleo
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Elisabetta Di Nicola
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Marialaura Latrofa
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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Brown TJ, Yablonovitch A, Till JE, Yen J, Kiedrowski LA, Hood R, O'Hara MH, Teitelbaum U, Karasic TB, Schneider C, Carpenter EL, Nathanson K, Domchek SM, Reiss KA. The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib. Clin Cancer Res 2023; 29:5207-5216. [PMID: 37486343 PMCID: PMC10806928 DOI: 10.1158/1078-0432.ccr-23-1467] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/13/2023] [Accepted: 07/20/2023] [Indexed: 07/25/2023]
Abstract
PURPOSE PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. EXPERIMENTAL DESIGN We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. RESULTS Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib. CONCLUSIONS Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.
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Affiliation(s)
- Timothy J Brown
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
- Penn Center for Cancer Care Innovation, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Jacob E Till
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | - Ryan Hood
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mark H O'Hara
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ursina Teitelbaum
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Thomas B Karasic
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Charles Schneider
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Erica L Carpenter
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Katherine Nathanson
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Susan M Domchek
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kim A Reiss
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
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Sun Y, Yang H, Yuan J, Wang L, Song S, Chen R, Bao X, Jia L, Yang T, Zhang X, He Q, Gan Y, Miao Z, He J, Yang C. YCH1899, a Highly Effective Phthalazin-1(2 H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors. J Med Chem 2023; 66:12284-12303. [PMID: 37605459 DOI: 10.1021/acs.jmedchem.3c00821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure-activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.
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Affiliation(s)
- Yuting Sun
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Hui Yang
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Jiaqi Yuan
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Limin Wang
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Shanshan Song
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Rongrong Chen
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046, China
| | - Xubin Bao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Li Jia
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Tiantian Yang
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Xiaofei Zhang
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - Qian He
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
| | - Yong Gan
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046, China
| | - Zehong Miao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Jinxue He
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Chunhao Yang
- State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
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9
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Doha ZO, Sears RC. Unraveling MYC's Role in Orchestrating Tumor Intrinsic and Tumor Microenvironment Interactions Driving Tumorigenesis and Drug Resistance. PATHOPHYSIOLOGY 2023; 30:400-419. [PMID: 37755397 PMCID: PMC10537413 DOI: 10.3390/pathophysiology30030031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 09/04/2023] [Accepted: 09/08/2023] [Indexed: 09/28/2023] Open
Abstract
The transcription factor MYC plays a pivotal role in regulating various cellular processes and has been implicated in tumorigenesis across multiple cancer types. MYC has emerged as a master regulator governing tumor intrinsic and tumor microenvironment interactions, supporting tumor progression and driving drug resistance. This review paper aims to provide an overview and discussion of the intricate mechanisms through which MYC influences tumorigenesis and therapeutic resistance in cancer. We delve into the signaling pathways and molecular networks orchestrated by MYC in the context of tumor intrinsic characteristics, such as proliferation, replication stress and DNA repair. Furthermore, we explore the impact of MYC on the tumor microenvironment, including immune evasion, angiogenesis and cancer-associated fibroblast remodeling. Understanding MYC's multifaceted role in driving drug resistance and tumor progression is crucial for developing targeted therapies and combination treatments that may effectively combat this devastating disease. Through an analysis of the current literature, this review's goal is to shed light on the complexities of MYC-driven oncogenesis and its potential as a promising therapeutic target.
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Affiliation(s)
- Zinab O. Doha
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA;
- Department of Medical Laboratories Technology, Taibah University, Al-Madinah 42353, Saudi Arabia
| | - Rosalie C. Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA;
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
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10
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Asiri MS, Dabaliz A, Almutairi M, Almahbub A, Alharbi M, Almeman S, AlShieban S, Alotaibi T, Algarni M. Complete Pathological Response to Platinum-Based Neoadjuvant Chemotherapy in BRCA2-Associated Locally Advanced Pancreatic Cancer: A Case Report and Literature Review. Cureus 2023; 15:e43261. [PMID: 37692681 PMCID: PMC10492221 DOI: 10.7759/cureus.43261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2023] [Indexed: 09/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease and is considered the fourth leading cause of death among cancer patients in the United States. Mutations in the BRCA gene, which is a DNA repair gene, increase the risk of PDAC, and among all patients with PDAC, about 8%-10% have a BRCA2 mutation. The finding of gene mutations is associated with a better response to platinum-based chemotherapy. Here, we present a case of a 59-year-old male with a BRCA2 gene mutation who was diagnosed with locally advanced pancreatic cancer and had achieved a complete pathological response to the FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) regimen and Whipple procedure. We also present our literature findings on response types in BRCA2 PDAC patients, as well as consensus on the use of different therapies. The use of platinum-based chemotherapy with BRCA2 is highly recommended as the first-line treatment. Most PDAC patients remain untested for BRCA2 mutation even though their genetic status influences the selection of drug regimens. Thus, we recommend genetic testing for everyone with PDAC.
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Affiliation(s)
- Mohamed S Asiri
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
- Medicine, King Abdullah International Medical Research Center, Riyadh, SAU
| | - Alhomam Dabaliz
- Medicine, College of Medicine, Alfaisal University, Riyadh, SAU
| | - Mahdi Almutairi
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | - Abdulaziz Almahbub
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | - Mohammed Alharbi
- Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Riyadh, SAU
| | - Sarah Almeman
- Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Riyadh, SAU
| | - Saeed AlShieban
- Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Riyadh, SAU
- Pathology and Laboratory Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
- Pathology and Laboratory Medicine, King Abdullah International Medical Research Center, Riyadh, SAU
| | - Tareq Alotaibi
- Medical Imaging, King Abdulaziz Medical City, Riyadh, Riyadh, SAU
| | - Mohammed Algarni
- Oncology, King Abdulaziz Medical City, Riyadh, Riyadh, SAU
- Oncology, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
- Oncology, King Abdullah International Medical Research Center, Riyadh, SAU
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11
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Wang SSY, Jie YE, Cheng SW, Ling GL, Ming HVY. PARP Inhibitors in Breast and Ovarian Cancer. Cancers (Basel) 2023; 15:cancers15082357. [PMID: 37190285 DOI: 10.3390/cancers15082357] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.
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Affiliation(s)
- Samuel S Y Wang
- Medical Oncology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Yeo Ee Jie
- Medical Oncology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Sim Wey Cheng
- Molecular Diagnostic Laboratory, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Goh Liuh Ling
- Molecular Diagnostic Laboratory, Tan Tock Seng Hospital, Singapore 308433, Singapore
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12
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Eswaran S, Padavu M, Kumar D, Kabekkodu SP. Systematic Analysis of the Therapy Resistance Genes and their Prognostic Relevance in Cervical Cancer. Curr Pharm Des 2023; 29:2018-2032. [PMID: 37584351 DOI: 10.2174/1381612829666230816100623] [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: 12/26/2022] [Revised: 06/12/2023] [Accepted: 07/14/2023] [Indexed: 08/17/2023]
Abstract
INTRODUCTION Critical issues in the therapeutic management of cervical cancer (CC) include therapy resistance and treatment failure. The development of therapy resistance is a multifaceted, progressive process, including genetic and epigenetic abnormalities. The present study aimed to identify genes that may contribute to therapy resistance in CC. MATERIALS AND METHODS We have created an extensive list of the genes in cancer that are therapy-resistant using a text-mining approach. The list was compared with the TCGA-CESC dataset to identify the differentially expressed therapy resistance genes (DETRGs) in CC. We used online resources (UALCAN, DNMIVD, cBio- Portal, HCMDB, OncoDB, ShinyGO, HPA, KM Plotter, TIMER, and DGIdb) to determine the potential association between methylation and expression of therapy resistance genes with the prognosis and clinical outcomes in CC. RESULTS The systematic analysis identified 71 out of 91 DETRGs showed aberrant DNA methylation. The overlapping analysis identified 25 genes to show an inverse correlation between methylation and expression. Further, differential expression or methylation could be helpful in CC staging, HPV association, prediction of metastasis and prognosis. The study identified seven driver genes in CC. The PPIN identifies ten hub genes (HGs) associated with CC staging, cancer hallmarks, and prognosis to affect long-term survival. CONCLUSION Our thorough investigation uncovered several novel genes and pathways that might contribute to therapy resistance in CC. The genes identified in our study may serve as a biomarker, prognostic indicator, and therapeutic target in CC.
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Affiliation(s)
- Sangavi Eswaran
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Mythili Padavu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
- Department of Entomology, UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Ave, Davis, CA95616, USA
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
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13
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Zhang H, Gao H, Gu Y, John A, Wei L, Huang M, Yu J, Adeosun AA, Weinshilboum RM, Wang L. 3D CRISPR screen in prostate cancer cells reveals PARP inhibitor sensitization through TBL1XR1-SMC3 interaction. Front Oncol 2022; 12:999302. [PMID: 36523978 PMCID: PMC9746894 DOI: 10.3389/fonc.2022.999302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/14/2022] [Indexed: 08/24/2023] Open
Abstract
Poly(ADP-ribose) (PAR) polymerase inhibitors (PARPi) either have been approved or being tested in the clinic for the treatment of a variety of cancers with homologous recombination deficiency (HRD). However, cancer cells can develop resistance to PARPi drugs through various mechanisms, and new biomarkers and combination therapeutic strategies need to be developed to support personalized treatment. In this study, a genome-wide CRISPR screen was performed in a prostate cancer cell line with 3D culture condition which identified novel signals involved in DNA repair pathways. One of these genes, TBL1XR1, regulates sensitivity to PARPi in prostate cancer cells. Mechanistically, we show that TBL1XR1 interacts with and stabilizes SMC3 on chromatin and promotes γH2AX spreading along the chromatin of the cells under DNA replication stress. TBL1XR1-SMC3 double knockdown (knockout) cells have comparable sensitivity to PARPi compared to SMC3 knockdown or TBL1XR1 knockout cells, and more sensitivity than WT cells. Our findings provide new insights into mechanisms underlying response to PARPi or platin compounds in the treatment of malignancies.
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Affiliation(s)
- Huan Zhang
- School of Medicine, Nantong University, Nantong, China
| | - Huanyao Gao
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Yayun Gu
- School of Medicine, Nantong University, Nantong, China
| | - August John
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Lixuan Wei
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Minhong Huang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Jia Yu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Adeyemi A. Adeosun
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Richard M. Weinshilboum
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Liewei Wang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
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14
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Kang J, Lee J, Lee A, Lee YS. Prediction of homologous recombination deficiency from cancer gene expression data. J Int Med Res 2022; 50:3000605221133655. [DOI: 10.1177/03000605221133655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Objective Homologous recombination deficiency (HRD) is the main mechanism of tumorigenesis in some cancers. HRD causes abnormal double-strand break repair, resulting in genomic scars. Some scoring HRD tests have been approved as companion diagnostics of polyadenosine diphosphate-ribose polymerase (PARP) inhibitor treatment. This study aimed to build an HRD prediction model using gene expression data from various cancer types. Methods The cancer genome atlas data were used for HRD prediction modeling. A total of 10,567 cases of 33 cancer types were included, and expression data from 5128 out of 20,502 genes were included as predictors. A penalized logistic regression model was chosen as a modeling technique. Results The area under the curve of the receiver operating characteristic curve of HRD status prediction was 0.98 for the training set and 0.93 for the test set. The accuracy of HRD status prediction was 0.93 for the training set and 0.88 for the test set. Conclusions Our study suggests that the HRD prediction model based on penalized logistic regression using gene expression data can be used to select patients for treatment with PARP inhibitors.
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Affiliation(s)
- Jun Kang
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Cancer Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Youn Soo Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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15
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Coelho R, Tozzi A, Disler M, Lombardo F, Fedier A, López MN, Freuler F, Jacob F, Heinzelmann-Schwarz V. Overlapping gene dependencies for PARP inhibitors and carboplatin response identified by functional CRISPR-Cas9 screening in ovarian cancer. Cell Death Dis 2022; 13:909. [PMID: 36307400 PMCID: PMC9616819 DOI: 10.1038/s41419-022-05347-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 11/23/2022]
Abstract
PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to progression-free survival, especially in patients either carrying BRCA1/2 mutations or harboring defects in the homologous recombination repair system. Yet, it remains uncertain which PARPi to apply and how to predict responders when platinum sensitivity is unknown. To shed light on the predictive power of genes previously suggested to be associated with PARPi response, we systematically reviewed the literature and identified 79 publications investigating a total of 93 genes. The top candidate genes were further tested using a comprehensive CRISPR-Cas9 mutagenesis screening in combination with olaparib treatment. Therefore, we generated six constitutive Cas9+ EOC cell lines and profiled 33 genes in a CRISPR-Cas9 cell competition assay using non-essential (AAVS1) and essential (RPA3 and PCNA) genes for cell fitness as negative and positive controls, respectively. We identified only ATM, MUS81, NBN, BRCA2, and RAD51B as predictive markers for olaparib response. As the major survival benefit of PARPi treatment was reported in platinum-sensitive tumors, we next assessed nine top candidate genes in combination with three PARPi and carboplatin. Interestingly, we observed similar dropout rates in a gene and compound independent manner, supporting the strong correlation of cancer cell response to compounds that rely on DNA repair for their effectiveness. In addition, we report on CDK12 as a common vulnerability for EOC cell survival and proliferation without altering the olaparib response, highlighting its potential as a therapeutic target in EOC.
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Affiliation(s)
- Ricardo Coelho
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Alessandra Tozzi
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland ,grid.410567.1Hospital for Women, University Hospital Basel, Basel, Switzerland
| | - Muriel Disler
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Flavio Lombardo
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - André Fedier
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Mónica Núñez López
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Florian Freuler
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Francis Jacob
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Viola Heinzelmann-Schwarz
- grid.410567.1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland ,grid.410567.1Hospital for Women, University Hospital Basel, Basel, Switzerland
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16
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Chu YY, Yam C, Yamaguchi H, Hung MC. Biomarkers beyond BRCA: promising combinatorial treatment strategies in overcoming resistance to PARP inhibitors. J Biomed Sci 2022; 29:86. [PMID: 36284291 PMCID: PMC9594904 DOI: 10.1186/s12929-022-00870-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit the concept of synthetic lethality and offer great promise in the treatment of tumors with deficiencies in homologous recombination (HR) repair. PARPi exert antitumor activity by blocking Poly(ADP-ribosyl)ation (PARylation) and trapping PARP1 on damaged DNA. To date, the U.S. Food and Drug Administration (FDA) has approved four PARPi for the treatment of several cancer types including ovarian, breast, pancreatic and prostate cancer. Although patients with HR-deficient tumors benefit from PARPi, majority of tumors ultimately develop acquired resistance to PARPi. Furthermore, even though BRCA1/2 mutations are commonly used as markers of PARPi sensitivity in current clinical practice, not all patients with BRCA1/2 mutations have PARPi-sensitive disease. Thus, there is an urgent need to elucidate the molecular mechanisms of PARPi resistance to support the development of rational effective treatment strategies aimed at overcoming resistance to PARPi, as well as reliable biomarkers to accurately identify patients who will most likely benefit from treatment with PARPi, either as monotherapy or in combination with other agents, so called marker-guided effective therapy (Mget). In this review, we summarize the molecular mechanisms driving the efficacy of and resistance to PARPi as well as emerging therapeutic strategies to overcome PARPi resistance. We also highlight the identification of potential markers to predict PARPi resistance and guide promising PARPi-based combination strategies.
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Affiliation(s)
- Yu-Yi Chu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Clinton Yam
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hirohito Yamaguchi
- Research Center for Cancer Biology, and Center for Molecular Medicine, Graduate Institute of Biomedical Sciences, China Medical University, 100, Sec 1, Jingmao Rd., Beitun, Taichung, 40402, Taiwan, ROC
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. .,Research Center for Cancer Biology, and Center for Molecular Medicine, Graduate Institute of Biomedical Sciences, China Medical University, 100, Sec 1, Jingmao Rd., Beitun, Taichung, 40402, Taiwan, ROC. .,Department of Biotechnology, Asia University, Taichung, 413, Taiwan.
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17
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Bisht P, Kumar VU, Pandey R, Velayutham R, Kumar N. Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development. Front Pharmacol 2022; 13:939570. [PMID: 35873570 PMCID: PMC9297740 DOI: 10.3389/fphar.2022.939570] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14-15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood-brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.
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Affiliation(s)
- Priya Bisht
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - V. Udaya Kumar
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - Ruchi Pandey
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - Ravichandiran Velayutham
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India
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18
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Li X, Yuan X, Wang Z, Li J, Liu Z, Wang Y, Wei L, Li Y, Wang X. Chidamide Reverses Fluzoparib Resistance in Triple-Negative Breast Cancer Cells. Front Oncol 2022; 12:819714. [PMID: 35251986 PMCID: PMC8894594 DOI: 10.3389/fonc.2022.819714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance is a new challenge for antitumor therapy. The purpose of this study was to investigate the reversal effects of chidamide on fluzoparib resistance, a PARPi, and its mechanism of action. A fluzoparib-resistant triple-negative breast cancer (TNBC) cell line was constructed, and the effects of chidamide and fluzoparib on drug-resistant cells were studied in vitro and in vivo. The effects of these drugs on cell proliferation, migration, invasiveness, the cell cycle, and apoptosis were detected using an MTT assay, wound-healing and transwell invasion assays, and flow cytometry. Bioinformatics was used to identify hub drug resistance genes and Western blots were used to assess the expression of PARP, RAD51, MRE11, cleaved Caspase9, and P-CDK1. Xenograft models were established to analyze the effects of these drugs on nude mice. In vivo results showed that chidamide combined with fluzoparib significantly inhibited the proliferation, migration, and invasiveness of drug-resistant cells and restored fluzoparib sensitivity to drug-resistant cells. The combination of chidamide and fluzoparib significantly inhibited the expression of the hub drug resistance genes RAD51 and MRE11, arrested the cell cycle at the G2/M phase, and induced cell apoptosis. The findings of this work show that chidamide combined with fluzoparib has good antineoplastic activity and reverses TNBC cell resistance to fluzoparil by reducing the expression levels of RAD51 and MRE11.
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Affiliation(s)
- Xinyang Li
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xiang Yuan
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Ziming Wang
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Jing Li
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Zhiwei Liu
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Yukun Wang
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Limin Wei
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Yuanpei Li
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, United States
| | - Xinshuai Wang
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
- *Correspondence: Xinshuai Wang,
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Therapeutic strategies to overcome cisplatin resistance in ovarian cancer. Eur J Med Chem 2022; 232:114205. [DOI: 10.1016/j.ejmech.2022.114205] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 12/15/2022]
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20
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Cleary JM, Wolpin BM, Dougan SK, Raghavan S, Singh H, Huffman B, Sethi NS, Nowak JA, Shapiro GI, Aguirre AJ, D'Andrea AD. Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma. Clin Cancer Res 2021; 27:6622-6637. [PMID: 34285063 PMCID: PMC8678153 DOI: 10.1158/1078-0432.ccr-21-1367] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/04/2021] [Accepted: 07/06/2021] [Indexed: 11/16/2022]
Abstract
Pancreatic cancer is rapidly progressive and notoriously difficult to treat with cytotoxic chemotherapy and targeted agents. Recent demonstration of the efficacy of maintenance PARP inhibition in germline BRCA mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Here, we review the potential mechanisms of exploiting HR deficiency, replicative stress, and DNA damage-mediated immune activation through targeted inhibition of DNA repair regulatory proteins.
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Affiliation(s)
- James M Cleary
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
| | - Brian M Wolpin
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Stephanie K Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Srivatsan Raghavan
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Harshabad Singh
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Brandon Huffman
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Nilay S Sethi
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Jonathan A Nowak
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Geoffrey I Shapiro
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Andrew J Aguirre
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Alan D D'Andrea
- Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts
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21
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Understanding and overcoming resistance to PARP inhibitors in cancer therapy. Nat Rev Clin Oncol 2021; 18:773-791. [PMID: 34285417 DOI: 10.1038/s41571-021-00532-x] [Citation(s) in RCA: 296] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2021] [Indexed: 02/07/2023]
Abstract
Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability.
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22
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Lai E, Ziranu P, Spanu D, Dubois M, Pretta A, Tolu S, Camera S, Liscia N, Mariani S, Persano M, Migliari M, Donisi C, Demurtas L, Pusceddu V, Puzzoni M, Scartozzi M. BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer 2021; 125:1321-1332. [PMID: 34262146 PMCID: PMC8575931 DOI: 10.1038/s41416-021-01469-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 05/28/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
- Department of Medical Oncology, Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussells, Belgium
| | - Simona Tolu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Silvia Camera
- Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicole Liscia
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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24
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Wattenberg MM, Reiss KA. Determinants of Homologous Recombination Deficiency in Pancreatic Cancer. Cancers (Basel) 2021; 13:4716. [PMID: 34572943 PMCID: PMC8466888 DOI: 10.3390/cancers13184716] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/10/2021] [Accepted: 09/16/2021] [Indexed: 12/23/2022] Open
Abstract
Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.
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Affiliation(s)
- Max M. Wattenberg
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kim A. Reiss
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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25
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Trunk A, Miotke L, Nevala-Plagemann C, Verdaguer H, Macarulla T, Garrido-Laguna I. Emerging Treatment Strategies in Pancreatic Cancer. Pancreas 2021; 50:773-787. [PMID: 34398070 DOI: 10.1097/mpa.0000000000001845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer death in well-developed countries. Therapeutic advances in PDAC to date have been modest. Recent progress to understand the molecular landscape of the disease has opened new treatment opportunities for a small subset of patients, frequently those with KRAS wild-type disease. Novel treatment strategies in PDAC include, among others, the use of nanotechnology and metabolic reprogramming. In addition, new strategies are being investigated, which are designed to overcome the resistance to checkpoint inhibitors, targeting DNA repair pathways including mismatch repair, increasing antigen presentation through the use of vaccines, targeting various signaling pathways, and reprogramming the tumor microenvironment. Here, we review the landscape of PDAC treatment strategies and some of these new agents.
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Affiliation(s)
- Andrew Trunk
- From the Department of Internal Medicine, University of Utah
| | - Laura Miotke
- From the Department of Internal Medicine, University of Utah
| | | | - Helena Verdaguer
- Division of Medical Oncology, Vall d'Hebrón University Hospital, Vall d'Hebrón Institute of Oncology, Barcelona, Spain
| | - Teresa Macarulla
- Division of Medical Oncology, Vall d'Hebrón University Hospital, Vall d'Hebrón Institute of Oncology, Barcelona, Spain
| | - Ignacio Garrido-Laguna
- Division of Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT
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26
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Golan T, O'Kane GM, Denroche RE, Raitses-Gurevich M, Grant RC, Holter S, Wang Y, Zhang A, Jang GH, Stossel C, Atias D, Halperin S, Berger R, Glick Y, Park JP, Cuggia A, Williamson L, Wong HL, Schaeffer DF, Renouf DJ, Borgida A, Dodd A, Wilson JM, Fischer SE, Notta F, Knox JJ, Zogopoulos G, Gallinger S. Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma. Gastroenterology 2021; 160:2119-2132.e9. [PMID: 33524400 DOI: 10.1053/j.gastro.2021.01.220] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 12/29/2020] [Accepted: 01/22/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
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Affiliation(s)
- Talia Golan
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Grainne M O'Kane
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Robert E Denroche
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Maria Raitses-Gurevich
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel
| | - Robert C Grant
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Spring Holter
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Yifan Wang
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; The Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada
| | - Amy Zhang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Gun Ho Jang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Chani Stossel
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dikla Atias
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sharon Halperin
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel
| | - Raanan Berger
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yulia Glick
- Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - J Patrick Park
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; The Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada
| | - Adeline Cuggia
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; The Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada
| | - Laura Williamson
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
| | - Hui-Li Wong
- BC Cancer, Vancouver Centre, Pancreas Centre BC, Canada
| | | | | | - Ayelet Borgida
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Anna Dodd
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Julie M Wilson
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Sandra E Fischer
- Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, Ontario, Canada
| | - Faiyaz Notta
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Jennifer J Knox
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - George Zogopoulos
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; The Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada
| | - Steven Gallinger
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
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27
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Noë M, Hong SM, Wood LD, Thompson ED, Roberts NJ, Goggins MG, Klein AP, Eshleman JR, Kern SE, Hruban RH. Pancreatic cancer pathology viewed in the light of evolution. Cancer Metastasis Rev 2021; 40:661-674. [PMID: 33555482 PMCID: PMC8556193 DOI: 10.1007/s10555-020-09953-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/30/2020] [Indexed: 12/14/2022]
Abstract
One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This “evolutionary view” creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.
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Affiliation(s)
- Michaël Noë
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Laura D Wood
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Elizabeth D Thompson
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Nicholas J Roberts
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Michael G Goggins
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Alison P Klein
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - James R Eshleman
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Scott E Kern
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ralph H Hruban
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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28
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Janysek DC, Kim J, Duijf PHG, Dray E. Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers. Transl Oncol 2021; 14:101012. [PMID: 33516088 PMCID: PMC7847957 DOI: 10.1016/j.tranon.2021.101012] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/14/2020] [Accepted: 12/31/2020] [Indexed: 12/11/2022] Open
Abstract
Cells are continuously subjected to DNA damaging agents. DNA damages are repaired by one of the many pathways guarding genomic integrity. When one or several DNA damage pathways are rendered inefficient, cells can accumulate mutations, which modify normal cellular pathways, favoring abnormal cell growth. This supports malignant transformation, which can occur when cells acquire resistance to cell cycle checkpoints, apoptosis, or growth inhibition signals. Mutations in genes involved in the repair of DNA double strand breaks (DSBs), such as BRCA1, BRCA2, or PALB2, significantly increase the risk of developing cancer of the breast, ovaries, pancreas, or prostate. Fortunately, the inability of these tumors to repair DNA breaks makes them sensitive to genotoxic chemotherapies, allowing for the development of therapies precisely tailored to individuals' genetic backgrounds. Unfortunately, as with many anti-cancer agents, drugs used to treat patients carrying a BRCA1 or BRCA2 mutation create a selective pressure, and over time tumors can become drug resistant. Here, we detail the cellular function of tumor suppressors essential in DNA damage repair pathways, present the mechanisms of action of inhibitors used to create synthetic lethality in BRCA carriers, and review the major molecular sources of drug resistance. Finally, we present examples of the many strategies being developed to circumvent drug resistance.
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Affiliation(s)
- Dawn C Janysek
- School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jennifer Kim
- School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Pascal H G Duijf
- Queensland University of Technology, IHBI at the Translational Research Institute, Brisbane, QLD, Australia; Centre for Data Science, Queensland University of Technology, Brisbane, QLD, Australia; University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Eloïse Dray
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX, United States.
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29
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Singh HM, Bailey P, Hübschmann D, Berger AK, Neoptolemos JP, Jäger D, Siveke J, Springfeld C. Poly(ADP-ribose) polymerase inhibition in pancreatic cancer. Genes Chromosomes Cancer 2021; 60:373-384. [PMID: 33341987 DOI: 10.1002/gcc.22932] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.
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Affiliation(s)
- Hans Martin Singh
- Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg, Germany
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.,Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Daniel Hübschmann
- Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Institute for Stem cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Anne Katrin Berger
- Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg, Germany
| | - John P Neoptolemos
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg, Germany
| | - Jens Siveke
- Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.,Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christoph Springfeld
- Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg, Germany
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30
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Thompson ED, Roberts NJ, Wood LD, Eshleman JR, Goggins MG, Kern SE, Klein AP, Hruban RH. The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go. Mod Pathol 2020; 33:2544-2563. [PMID: 32704031 PMCID: PMC8375585 DOI: 10.1038/s41379-020-0629-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/07/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022]
Abstract
The publication of the "Pan-Cancer Atlas" by the Pan-Cancer Analysis of Whole Genomes Consortium, a partnership formed by The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), provides a wonderful opportunity to reflect on where we stand in our understanding of the genetics of pancreatic cancer, as well as on the opportunities to translate this understanding to patient care. From germline variants that predispose to the development of pancreatic cancer, to somatic mutations that are therapeutically targetable, genetics is now providing hope, where there once was no hope, for those diagnosed with pancreatic cancer.
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Affiliation(s)
- Elizabeth D Thompson
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicholas J Roberts
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James R Eshleman
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael G Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Scott E Kern
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alison P Klein
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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31
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Shnaider PV, Ivanova OM, Malyants IK, Anufrieva KS, Semenov IA, Pavlyukov MS, Lagarkova MA, Govorun VM, Shender VO. New Insights into Therapy-Induced Progression of Cancer. Int J Mol Sci 2020; 21:E7872. [PMID: 33114182 PMCID: PMC7660620 DOI: 10.3390/ijms21217872] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.
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Affiliation(s)
- Polina V. Shnaider
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Olga M. Ivanova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
| | - Irina K. Malyants
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Faculty of Chemical-Pharmaceutical Technologies and Biomedical Drugs, Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia
| | - Ksenia S. Anufrieva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Moscow Institute of Physics and Technology (State University), Dolgoprudny 141701, Russia
| | - Ilya A. Semenov
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
| | - Marat S. Pavlyukov
- Laboratory of Membrane Bioenergetics, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia;
| | - Maria A. Lagarkova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
| | - Vadim M. Govorun
- Laboratory of Simple Systems, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia;
| | - Victoria O. Shender
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia; (P.V.S.); (O.M.I.); (K.S.A.); (M.A.L.)
- Laboratory of Cell Biology, Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, Russia; (I.K.M.); (I.A.S.)
- Laboratory of Molecular Oncology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
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32
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Tobalina L, Armenia J, Irving E, O'Connor MJ, Forment JV. A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann Oncol 2020; 32:103-112. [PMID: 33091561 DOI: 10.1016/j.annonc.2020.10.470] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/27/2020] [Accepted: 10/04/2020] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild-type BRCA gene, which makes them exquisitely sensitive to platinum drugs and poly(ADP-ribose) polymerase inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments. PATIENTS AND METHODS We analysed published sequencing data of BRCA genes (from tumour or circulating tumour DNA) in 327 patients with tumours harbouring mutations in BRCA1 or BRCA2 (234 patients with ovarian cancer, 27 with breast cancer, 13 with pancreatic cancer, 11 with prostate cancer and 42 with a cancer of unknown origin) that progressed on platinum or PARPi treatment. RESULTS We describe 269 cases of reversion mutations in 86 patients in this cohort (26.0%). Detailed analyses of the reversion events highlight that most amino acid sequences encoded by exon 11 in BRCA1 and BRCA2 are dispensable to generate resistance to platinum or PARPi, whereas other regions are more refractory to sizeable amino acid losses. They also underline the key role of mutagenic end-joining DNA repair pathways in generating reversions, especially in those affecting BRCA2, as indicated by the significant accumulation of DNA sequence microhomologies surrounding deletions leading to reversion events. CONCLUSIONS Our analyses suggest that pharmacological inhibition of DNA end-joining repair pathways could improve durability of drug treatments by preventing the acquisition of reversion mutations in BRCA genes. They also highlight potential new therapeutic opportunities when reversions result in expression of hypomorphic versions of BRCA proteins, especially with agents targeting the response to DNA replication stress.
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Affiliation(s)
- L Tobalina
- Bioinformatics and Data Science, Oncology R&D, AstraZeneca, Cambridge, UK
| | - J Armenia
- Bioinformatics and Data Science, Oncology R&D, AstraZeneca, Cambridge, UK
| | - E Irving
- DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
| | - M J O'Connor
- DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
| | - J V Forment
- DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
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33
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Pettitt SJ, Frankum JR, Punta M, Lise S, Alexander J, Chen Y, Yap TA, Haider S, Tutt ANJ, Lord CJ. Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance. Cancer Discov 2020; 10:1475-1488. [PMID: 32699032 PMCID: PMC7611203 DOI: 10.1158/2159-8290.cd-19-1485] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/16/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion "hotspots" and "deserts" in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most reversions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA-repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA-mutant cancers. SIGNIFICANCE: Reversion mutations in BRCA genes are a major cause of clinical platinum and PARP inhibitor resistance. This analysis of all reported clinical reversions suggests that the position of BRCA2 mutations affects the risk of reversion. Many reversions are also predicted to encode tumor neoantigens, providing a potential route to targeting resistance.This article is highlighted in the In This Issue feature, p. 1426.
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Affiliation(s)
- Stephen J Pettitt
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom.
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Jessica R Frankum
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Marco Punta
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Stefano Lise
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - John Alexander
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Yi Chen
- Scientific Computing Team, The Institute of Cancer Research, London, United Kingdom
| | - Timothy A Yap
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Syed Haider
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Andrew N J Tutt
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Christopher J Lord
- The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom.
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
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34
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Chen HD, Guo N, Song SS, Chen CH, Miao ZH, He JX. Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors. Am J Cancer Res 2020; 10:2813-2831. [PMID: 33042619 PMCID: PMC7539764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 07/23/2020] [Indexed: 06/11/2023] Open
Abstract
Several poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) have been approved for cancer therapy; however, intrinsic and acquired resistance has limited their efficacy in the clinic. In fact, cancer cells have developed multiple mechanisms to overcome PARPi cytotoxicity in even a single cancer cell. In this study, we generated three PARPi-resistant BRCA2-deficient pancreatic Capan-1 variant cells using olaparib (Capan-1/OP), talazoparib (Capan-1/TP), and simmiparib (Capan-1/SP). We identified novel mutations in intron 11 of BRCA2, which resulted in the expression of truncated BRCA2 splice isoforms. Functional studies revealed that only a fraction (32-49%) of PARPi sensitivity could be rescued by depletion of BRCA2 isoforms. In addition, the apoptosis signals (phosphatidylserine eversion, caspase 3/7/8/9 activation, and mitochondrial membrane potential loss) were almost completely abrogated in all PARPi-resistant variants. Consistently, overexpression of the anti-apoptotic proteins cyclooxygenase 2 (COX-2) and baculoviral IAP repeat-containing 3 (BIRC3) occurred in these variants. Depletion of COX-2 or BIRC3 significantly reduced apoptotic resistance in the PARPi-resistant sublines and reversed PARPi resistance by up to 70-72%. Furthermore, exogenous addition of prostaglandin E2, a major metabolic product of COX-2, inhibited PARPi-induced apoptotic signals; however, when combined with the BIRC3 inhibitor LCL161, there was significantly enhanced sensitivity of the resistant variants to PARPi. Finally, PARPi treatment or PARP1 depletion led to a marked increase in the mRNA and protein levels of COX-2 and BIRC3, indicating that PARP1 is a negative transcriptional regulator of these proteins. Together, our findings demonstrated that during the chronic treatment of cells with a PARPi, both BRCA2 intron 11 mutations and COX-2/BIRC3-mediated apoptotic resistance led to PARPi resistance in pancreatic Capan-1 cells.
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Affiliation(s)
- Hua-Dong Chen
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai 201203, P. R. China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
| | - Ne Guo
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai 201203, P. R. China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
| | - Shan-Shan Song
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai 201203, P. R. China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
| | - Chuan-Huizi Chen
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai 201203, P. R. China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
| | - Ze-Hong Miao
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai 201203, P. R. China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
- Open Studio for Drugability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao)1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, Shandong, P. R. China
| | - Jin-Xue He
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai 201203, P. R. China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
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35
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Li H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer 2020; 19:107. [PMID: 32563252 PMCID: PMC7305609 DOI: 10.1186/s12943-020-01227-0] [Citation(s) in RCA: 284] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/11/2020] [Indexed: 12/31/2022] Open
Abstract
Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity.
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Affiliation(s)
- He Li
- Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China
| | - Zhao-Yi Liu
- Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China
| | - Nayiyuan Wu
- Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China
| | - Yong-Chang Chen
- Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Jing Wang
- Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China. .,Department of Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China.
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36
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Cleary JM, Aguirre AJ, Shapiro GI, D'Andrea AD. Biomarker-Guided Development of DNA Repair Inhibitors. Mol Cell 2020; 78:1070-1085. [PMID: 32459988 PMCID: PMC7316088 DOI: 10.1016/j.molcel.2020.04.035] [Citation(s) in RCA: 172] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/02/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023]
Abstract
Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.
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Affiliation(s)
- James M Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Geoffrey I Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Alan D D'Andrea
- Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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37
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Golan T, Brody JR. Targeting homologous recombination addicted tumors: challenges and opportunities. ANNALS OF PANCREATIC CANCER 2020; 3:6. [PMID: 35441131 PMCID: PMC9015682 DOI: 10.21037/apc.2020.03.02] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Recent advances in next generation sequencing (NGS) and molecular subtyping of tumors have opened the door to clinically available targeted therapies. Although the treatment of many solid tumors still rely on a steady regimen of non-targeted chemotherapeutic agents, it is becoming increasingly more apparent that certain tumors with defects in DNA damage repair (DDR) genes may be exquisitely sensitive to DNA damaging agents or therapies targeting key elements of this pathway such PARP1, ATR, or ATM. Still, for tumors with DDR defects the challenges are multi-fold including: (I) identifying these tumors in patients in time for a window of opportunity of treatment; (II) ensuring that these tumors are still reliant or addicted to this pathway; and (III) making sure these tumors are matched with the precise treatment option. Herein, we will discuss the opportunities, challenges, and future of targeting a subset of DDR-defective tumors.
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Affiliation(s)
- Talia Golan
- Oncology Institute, Chaim Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jonathan R. Brody
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
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38
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Tao H, Liu S, Huang D, Han X, Wu X, Shao YW, Hu Y. Acquired multiple secondary BRCA2 mutations upon PARPi resistance in a metastatic pancreatic cancer patient harboring a BRCA2 germline mutation. Am J Transl Res 2020; 12:612-617. [PMID: 32194909 PMCID: PMC7061843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 01/17/2020] [Indexed: 06/10/2023]
Abstract
PARP inhibitor (PARPi) therapies have been approved for treating multiple germline BRCA mutated (gBRCAm) advanced cancers including metastatic pancreatic cancer. Although significantly prolonged progression-free survival was observed in gBRCAm pancreatic cancer patients, there was no improved overall survival. The underlined resistant mechanism to PARPi therapy is worth pursuing. Here, we reported a patient with advanced pancreatic cancer harboring a germline deleterious BRCA2 V1804Kfs mutation as well as somatic mutations in KRAS, TP53 and PTEN. Stable disease was achieved with the combination therapy of cisplatin and PARPi olaparib, but the disease quickly progressed after 18 weeks of treatment. Next-generation sequencing (NGS)-based genomic profiling of the liver metastasis and liquid biopsy revealed four newly acquired BRCA2 indel mutations, including two reversion mutations that could potentially restore BRCA2 function in the PARPi-resistant tumor. Our case showed that although initial response to PARPi therapy can be achieved in advanced gBRCAm pancreatic cancer patient, the tumor rapidly evolved to acquire multiple secondary BRCA2 mutations to restore the integrity of DNA repair and confer drug resistance, which may contribute to the unimproved overall survival in pancreatic cancer patients.
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Affiliation(s)
- Haitao Tao
- The First Medical Center of Chinese PLA General HospitalBeijing, China
| | - Sisi Liu
- Department of R&D, Nanjing Geneseeq Technology Inc.Nanjing, Jiangsu, China
| | - Di Huang
- The First Medical Center of Chinese PLA General HospitalBeijing, China
| | - Xiao Han
- The First Medical Center of Chinese PLA General HospitalBeijing, China
| | - Xue Wu
- Translational Medicine Research Institute, Geneseeq Technology Inc.Toronto, Ontario, Canada
| | - Yang W Shao
- Department of R&D, Nanjing Geneseeq Technology Inc.Nanjing, Jiangsu, China
- School of Public Health, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Yi Hu
- The First Medical Center of Chinese PLA General HospitalBeijing, China
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39
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Vidula N, Rich TA, Sartor O, Yen J, Hardin A, Nance T, Lilly MB, Nezami MA, Patel SP, Carneiro BA, Fan AC, Brufsky AM, Parker BA, Bridges BB, Agarwal N, Maughan BL, Raymond VM, Fairclough SR, Lanman RB, Bardia A, Cristofanilli M. Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors. Clin Cancer Res 2020; 26:2546-2555. [DOI: 10.1158/1078-0432.ccr-19-2933] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/17/2019] [Accepted: 02/03/2020] [Indexed: 11/16/2022]
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Abstract
In this review, Slade provides an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. The author also highlights the clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discusses the predictive biomarkers of inhibitor sensitivity and mechanisms of resistance as well as the means of overcoming them through combination therapy. Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.
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Affiliation(s)
- Dea Slade
- Department of Biochemistry, Max Perutz Labs, Vienna Biocenter (VBC), University of Vienna, 1030 Vienna, Austria
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41
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Khalique S, Pettitt SJ, Kelly G, Tunariu N, Natrajan R, Banerjee S, Lord CJ. Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR. J Pathol Clin Res 2020; 6:3-11. [PMID: 31577852 PMCID: PMC6966703 DOI: 10.1002/cjp2.146] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/13/2019] [Accepted: 09/16/2019] [Indexed: 01/31/2023]
Abstract
Development of resistance to platinum and poly(ADP-ribose) polymerase inhibitors via secondary BRCA gene mutations that restore functional homologous recombination has been observed in a number of cancer types. Here we report a case of somatic BRCA2 mutation in a patient with high grade serous ovarian carcinoma. A secondary mutation predicted to restore the BRCA2 open reading frame was detected at low frequency (2.3%) in whole exome sequencing of a peritoneal biopsy at disease progression after treatment that included carboplatin and olaparib. We used digital droplet PCR (ddPCR) to verify the presence and frequency of this mutation in the biopsy sample at progression and also used this approach to assess the presence of the secondary mutation in preceding biopsies at diagnosis and first relapse. We found no evidence for the secondary mutation being present prior to the final progression biopsy, suggesting that this mutation was acquired late in the course of treatment. ddPCR provides a sensitive and specific technique to investigate the presence of low frequency mutations in a time series of biopsies.
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Affiliation(s)
- Saira Khalique
- Division of Molecular PathologyThe Institute of Cancer ResearchLondonUK
- The Breast Cancer Now Toby Robins Research CentreThe Institute of Cancer ResearchLondonUK
- The Royal Marsden NHS Foundation Trust and The Institute of Cancer ResearchSuttonUK
| | - Stephen J Pettitt
- The CRUK Gene Function Laboratory and Breast Cancer Now Research CentreThe Institute of Cancer ResearchLondonUK
| | - Ger Kelly
- The CRUK Gene Function Laboratory and Breast Cancer Now Research CentreThe Institute of Cancer ResearchLondonUK
| | - Nina Tunariu
- The Royal Marsden NHS Foundation Trust and The Institute of Cancer ResearchSuttonUK
| | - Rachael Natrajan
- Division of Molecular PathologyThe Institute of Cancer ResearchLondonUK
| | - Susana Banerjee
- The Royal Marsden NHS Foundation Trust and The Institute of Cancer ResearchSuttonUK
| | - Christopher J Lord
- The CRUK Gene Function Laboratory and Breast Cancer Now Research CentreThe Institute of Cancer ResearchLondonUK
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42
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Meijer TG, Verkaik NS, van Deurzen CHM, Dubbink HJ, den Toom TD, Sleddens HFBM, De Hoop EO, Dinjens WNM, Kanaar R, van Gent DC, Jager A. Direct Ex Vivo Observation of Homologous Recombination Defect Reversal After DNA-Damaging Chemotherapy in Patients With Metastatic Breast Cancer. JCO Precis Oncol 2019; 3:1-12. [PMID: 35100677 DOI: 10.1200/po.18.00268] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Biomarkers that predict response to poly (ADP-ribose) polymerase inhibitors (PARPis) are required to detect PARPi sensitivity beyond germline BRCA-mutated (gBRCAm) cancers and PARPi resistance among reverted gBRCAm cancers. Therefore, we previously developed the Repair Capacity (RECAP) test, a functional homologous recombination (HR) assay that exploits the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh primary breast cancer tissue. The aim of the current study was to validate the feasibility of this test on histologic biopsy specimens from metastatic breast cancer and to explore the utility of the RECAP test as a predictive tool for treatment with DNA-damaging agents, such as PARPis. METHODS Fresh tissue biopsies from easily accessible metastatic lesions from patients with locally advanced or metastatic breast cancer were irradiated with 5 Gy and cultured for 2 hours followed by detection of RAD51 foci presence (HR proficient) or absence (HR deficient [HRD]). HRD biopsy specimens as well as platinum/PARP-resistant specimens were subjected to BRCA1/2 sequencing. RESULTS RECAP had a success rate of 93% on biopsy specimens from metastatic breast cancer lesions (n = 44). Although HRD was detected in 13 (32%) of 41 specimens, only five showed a gBRCAm. In three patients with gBRCAm, post-treatment RECAP tests showed HR phenotype reversion after in vivo progressive disease on platinum and PARPi treatment, which was explained in one patient by a secondary BRCA1 mutation. CONCLUSION The RECAP test, which reflects real-time HR status regardless of BRCA mutations, is feasible in metastatic breast cancer biopsy specimens. Compared with gBRCA analysis, it may identify twice as many candidates for PARPi treatment.
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Affiliation(s)
- Titia G Meijer
- Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Nicole S Verkaik
- Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | | | | | | | | | | | | | - Roland Kanaar
- Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Dik C van Gent
- Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Agnes Jager
- Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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Rebelatto TF, Falavigna M, Pozzari M, Spada F, Cella CA, Laffi A, Pellicori S, Fazio N. Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis. Cancer Treat Rev 2019; 80:101895. [PMID: 31542591 DOI: 10.1016/j.ctrv.2019.101895] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). MATERIAL AND METHODS The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. RESULTS Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). CONCLUSION Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.
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Affiliation(s)
- Taiane F Rebelatto
- Department of Medical Oncology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Maicon Falavigna
- National Institute for Heath Technology Assessment, Postgraduate Program in Epidemiology, Porto Alegre, Brazil
| | - Marta Pozzari
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Chiara A Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Stefania Pellicori
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
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44
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Jain A, Agostini LC, McCarthy GA, Chand SN, Ramirez A, Nevler A, Cozzitorto J, Schultz CW, Lowder CY, Smith KM, Waddell ID, Raitses-Gurevich M, Stossel C, Gorman YG, Atias D, Yeo CJ, Winter JM, Olive KP, Golan T, Pishvaian MJ, Ogilvie D, James DI, Jordan AM, Brody JR. Poly (ADP) Ribose Glycohydrolase Can Be Effectively Targeted in Pancreatic Cancer. Cancer Res 2019; 79:4491-4502. [PMID: 31273064 PMCID: PMC6816506 DOI: 10.1158/0008-5472.can-18-3645] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/06/2019] [Accepted: 07/01/2019] [Indexed: 12/20/2022]
Abstract
Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than 1 year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (ELAVL1). Here, we evaluated PARG as a target in PDAC models using both genetic silencing of PARG and established small-molecule PARG inhibitors (PARGi), PDDX-01/04. Homologous repair-deficient cells compared with homologous repair-proficient cells were more sensitive to PARGi in vitro. In vivo, silencing of PARG significantly decreased tumor growth. PARGi synergized with DNA-damaging agents (i.e., oxaliplatin and 5-fluorouracil), but not with PARPi therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased γH2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi. SIGNIFICANCE: PARG is a potential target in pancreatic cancer as a single-agent anticancer therapy or in combination with current standard of care.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Lebaron C Agostini
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Grace A McCarthy
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Saswati N Chand
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - AnnJosette Ramirez
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Avinoam Nevler
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Joseph Cozzitorto
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Christopher W Schultz
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Cinthya Yabar Lowder
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Kate M Smith
- Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | - Ian D Waddell
- Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | | | - Chani Stossel
- Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yulia Glick Gorman
- Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Dikla Atias
- Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Charles J Yeo
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jordan M Winter
- Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Kenneth P Olive
- Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Talia Golan
- Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael J Pishvaian
- Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Donald Ogilvie
- Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | - Dominic I James
- Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | - Allan M Jordan
- Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | - Jonathan R Brody
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
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45
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Noordermeer SM, van Attikum H. PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells. Trends Cell Biol 2019; 29:820-834. [PMID: 31421928 DOI: 10.1016/j.tcb.2019.07.008] [Citation(s) in RCA: 308] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities.
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Affiliation(s)
- Sylvie M Noordermeer
- Leiden University Medical Center, Department of Human Genetics, Einthovenweg 20, 2333 ZC Leiden, The Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands.
| | - Haico van Attikum
- Leiden University Medical Center, Department of Human Genetics, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
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46
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Hoppe MM, Sundar R, Tan DSP, Jeyasekharan AD. Biomarkers for Homologous Recombination Deficiency in Cancer. J Natl Cancer Inst 2019; 110:704-713. [PMID: 29788099 DOI: 10.1093/jnci/djy085] [Citation(s) in RCA: 232] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/06/2018] [Indexed: 12/11/2022] Open
Abstract
Defective DNA repair is a common hallmark of cancer. Homologous recombination is a DNA repair pathway of clinical interest due to the sensitivity of homologous recombination-deficient cells to poly-ADP ribose polymerase (PARP) inhibitors. The measurement of homologous recombination deficiency (HRD) in cancer is therefore vital to the appropriate design of clinical trials incorporating PARP inhibitors. However, methods to identify HRD in tumors are varied and controversial. Understanding existing and new methods to measure HRD is important to their appropriate use in clinical trials and practice. The aim of this review is to summarize the biology and clinical validation of current methods to measure HRD, to aid decision-making for patient stratification and translational research in PARP inhibitor trials. We discuss the current clinical development of PARP inhibitors, along with established indicators for HRD such as germline BRCA1/2 mutation status and clinical response to platinum-based therapy. We then examine newer assays undergoing clinical validation, including 1) somatic mutations in homologous recombination genes, 2) "genomic scar" assays using array-based comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) analysis or mutational signatures derived from next-generation sequencing, 3) transcriptional profiles of HRD, and 4) phenotypic or functional assays of protein expression and localization. We highlight the strengths and weaknesses of each of these assays, for consideration during the design of studies involving PARP inhibitors.
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Affiliation(s)
- Michal M Hoppe
- Cancer Science Institute of Singapore, National University Hospital, Singapore
| | - Raghav Sundar
- Department of Haematology-Oncology, National University Hospital, Singapore
| | - David S P Tan
- Cancer Science Institute of Singapore, National University Hospital, Singapore.,Department of Haematology-Oncology, National University Hospital, Singapore
| | - Anand D Jeyasekharan
- Cancer Science Institute of Singapore, National University Hospital, Singapore.,Department of Haematology-Oncology, National University Hospital, Singapore
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47
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Gogola E, Rottenberg S, Jonkers J. Resistance to PARP Inhibitors: Lessons from Preclinical Models of BRCA-Associated Cancer. ANNUAL REVIEW OF CANCER BIOLOGY 2019; 3:235-254. [DOI: 10.1146/annurev-cancerbio-030617-050232] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Inhibitors of poly(ADP-ribose) polymerase (PARP) have recently entered the clinic for the treatment of homologous recombination–deficient cancers. Despite the success of this approach, resistance to PARP inhibitors (PARPis) is a clinical hurdle, and it is poorly understood how cancer cells escape the deadly effects of PARPis without restoring BRCA1/2 function. By synergizing the advantages of next-generation sequencing with functional genetic screens in tractable model systems, novel mechanisms providing useful insights into DNA damage response (DDR) have been identified. BRCA1/2 models not only are tools to explore therapy escape mechanisms but also yield basic knowledge about DDR pathways and PARPis’ mechanism of action. Moreover, alterations that render cells resistant to targeted therapies may cause new synthetic dependencies that can be exploited to combat resistant disease.
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Affiliation(s)
- Ewa Gogola
- Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Cancer Genomics Centre Netherlands, 3584 CG Utrecht, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Sven Rottenberg
- Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
| | - Jos Jonkers
- Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Cancer Genomics Centre Netherlands, 3584 CG Utrecht, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
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48
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Heczkova M, Machackova E, Macinga P, Gallmeier E, Cahova M, Spicak J, Jirsa M, Foretova L, Hucl T. Functional evaluation of variants of unknown significance in the BRCA2 gene identified in genetic testing. Cancer Biol Ther 2019; 20:633-641. [PMID: 30638113 DOI: 10.1080/15384047.2018.1550566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance or prophylactic surgery. Besides clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. The influence of such variants on cancer risk is often unknown, making their presence a major clinical problem. When genetic methods are insufficient to classify these variants, functional assays with various cellular models are performed. We developed and applied a new syngeneic model of human cancer cells to test all variants of unknown significance in exon 18 identified by genetic testing of high-risk cancer patients in the Czech Republic, via introduction of constructs containing each of these variants into the wild-type allele of BRCA2-heterozygous DLD1 cells (BRCA2wt/Δex11). We found unaffected DNA repair function of BRCA2 in cell lines BRCA27997G>C/Δex11, BRCA28111C>T/Δex11, BRCA28149G>T/Δex11, BRCA28182G>A/Δex11, and BRCA28182G>T/Δex11, whereas the cell line BRCA28168A>G/Δex11 and the nonsense mutation carrying line BRCA28305G>T/Δex11 did affect protein function. Targeting the BRCA2 wild-type allele with a construct carrying the variant c.7988A> G resulted in incorporation exclusively into the already defective allele in all viable clones, strongly suggesting a detrimental phenotype. Our model thus offers a valuable tool for the functional evaluation of unclassified variants in the BRCA2 gene and provides a stable and distributable cellular resource for further research.
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Affiliation(s)
- Marie Heczkova
- a Center for Experimental Medicine , Institute of Clinical and Experimental Medicine , Prague , Czech Republic
| | - Eva Machackova
- b Department of Cancer Epidemiology and Genetics , Masaryk Memorial Cancer Institute , Brno , Czech Republic
| | - Peter Macinga
- c Department of Gastroenterology and Hepatology , Institute of Clinical and Experimental Medicine , Prague , Czech Republic
| | - Eike Gallmeier
- d Department of Internal Medicine , Philipps University of Marburg , Marburg , Germany
| | - Monika Cahova
- a Center for Experimental Medicine , Institute of Clinical and Experimental Medicine , Prague , Czech Republic
| | - Julius Spicak
- c Department of Gastroenterology and Hepatology , Institute of Clinical and Experimental Medicine , Prague , Czech Republic
| | - Milan Jirsa
- a Center for Experimental Medicine , Institute of Clinical and Experimental Medicine , Prague , Czech Republic
| | - Lenka Foretova
- b Department of Cancer Epidemiology and Genetics , Masaryk Memorial Cancer Institute , Brno , Czech Republic
| | - Tomas Hucl
- a Center for Experimental Medicine , Institute of Clinical and Experimental Medicine , Prague , Czech Republic.,c Department of Gastroenterology and Hepatology , Institute of Clinical and Experimental Medicine , Prague , Czech Republic
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49
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Pishvaian MJ, Petricoin E. Molecular Profiling of Pancreatic Cancer Patients-Response. Clin Cancer Res 2018; 24:6612. [PMID: 30552237 DOI: 10.1158/1078-0432.ccr-18-2645] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 08/17/2018] [Accepted: 08/17/2018] [Indexed: 11/16/2022]
Affiliation(s)
- Michael J Pishvaian
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, D.C.
- Perthera, Inc, McLean, Virginia
| | - Emanuel Petricoin
- Perthera, Inc, McLean, Virginia
- George Mason University, Fairfax, Virginia
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50
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Schiewer MJ, Mandigo AC, Gordon N, Huang F, Gaur S, de Leeuw R, Zhao SG, Evans J, Han S, Parsons T, Birbe R, McCue P, McNair C, Chand SN, Cendon-Florez Y, Gallagher P, McCann JJ, Poudel Neupane N, Shafi AA, Dylgjeri E, Brand LJ, Visakorpi T, Raj GV, Lallas CD, Trabulsi EJ, Gomella LG, Dicker AP, Kelly WK, Leiby BE, Knudsen B, Feng FY, Knudsen KE. PARP-1 regulates DNA repair factor availability. EMBO Mol Med 2018; 10:e8816. [PMID: 30467127 PMCID: PMC6284389 DOI: 10.15252/emmm.201708816] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 10/10/2018] [Accepted: 10/25/2018] [Indexed: 12/22/2022] Open
Abstract
PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance "BRCA-ness". These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.
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Affiliation(s)
- Matthew J Schiewer
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Amy C Mandigo
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Nicolas Gordon
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | | | | | - Renée de Leeuw
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Shuang G Zhao
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Joseph Evans
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Sumin Han
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Theodore Parsons
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ruth Birbe
- Cooper University Health, Camden, NJ, USA
| | - Peter McCue
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Christopher McNair
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Saswati N Chand
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Ylenia Cendon-Florez
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Peter Gallagher
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Jennifer J McCann
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Neermala Poudel Neupane
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Ayesha A Shafi
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Emanuela Dylgjeri
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucas J Brand
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | | | | | - Costas D Lallas
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Edouard J Trabulsi
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Leonard G Gomella
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam P Dicker
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Wm Kevin Kelly
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Benjamin E Leiby
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Felix Y Feng
- Departments of Radiation Oncology, Urology, and Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Karen E Knudsen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
- Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
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