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Canale M, Urbini M, Petracci E, Angeli D, Tedaldi G, Priano I, Cravero P, Flospergher M, Andrikou K, Bennati C, Tassinari D, Dubini A, Rossi G, Panzacchi R, Valli M, Bronte G, Crinò L, Delmonte A, Ulivi P. Genomic Profiling of Extensive Stage Small-Cell Lung Cancer Patients Identifies Molecular Factors Associated with Survival. LUNG CANCER (AUCKLAND, N.Z.) 2025; 16:11-23. [PMID: 39995768 PMCID: PMC11849429 DOI: 10.2147/lctt.s492825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 01/11/2025] [Indexed: 02/26/2025]
Abstract
Objective Extensive stage Small-Cell Lung Cancer (ES-SCLC) is the most lethal lung cancer, and the addition of immunotherapy conferred a slight survival benefit for patients. Extensive molecular profiling of patients treated with chemotherapy (CT) or chemotherapy plus immunotherapy (CT+IO) would be able to identify molecular factors associated with patients' survival. Material and Methods In this retrospective study, 99 ES-SCLC patients were considered. Of the 79 includible patients, 42 received CT (median age 71 y/o, I-IIIQ: 65-76), and 37 received CT+IO (median age 71 y/o, I-IIIQ 66-75). The FoundationOne CDx assay was performed on patients' tumor tissues. Results The most mutated genes were TP53 (99%), RB1 (78%), PTEN (23%) and MLL2 (20%), with no significant differences between the treatment groups. As a continuous variable, Tumor Mutation Burden (TMB) had an effect on patients' progression-free survival (PFS) by type of treatment (HR 1.81 (95%, CI: 0.99-3.31) and HR 0.84 (95%, CI: 0.56-1.26) for patients treated with CT and CT+IO, respectively). TMB was also computed and dichotomized using two different cut-offs: considering cut-offs of 10 mut/Mb and >16 mut/Mb, 45 patients (57%) and 68 patients (86.1%) had a low TMB, respectively. A high TMB (cut-off 10 mut/Mb) predicted worse PFS in patients treated with CT (p=0.046); even though not statistically significant, a high TMB (cut-off 16 mut/Mb) predicted a better survival in patients treated with CT+IO. Moreover, at univariate analysis, MLL2 mutations were associated with better prognosis in the overall case series (HRPFS = 0.51, 95% CI: 0.28-0.94), and overall survival (HROS = 0.52, 95% CI: 0.28-0.97). Conclusion In ES-SCLC, TMB is associated with worse survival in patients treated with CT alone, and with better survival in patients treated with CT+IO, whether considered as a continuous or a dichotomized variable, at different cut-offs. Alterations in epigenetic factors are also associated to better patient prognosis.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) “dino Amadori”, Meldola, Italy
| | - Milena Urbini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) “dino Amadori”, Meldola, Italy
| | - Elisabetta Petracci
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Davide Angeli
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Gianluca Tedaldi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) “dino Amadori”, Meldola, Italy
| | - Ilaria Priano
- Department of Medical Oncology, Vall d´Hebron Institute of Oncology (VHIO), Vall d’Hebron Hospital Universitari, Barcelona, Spain
| | - Paola Cravero
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, 47014, Italy
| | - Michele Flospergher
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, 47014, Italy
| | - Kalliopi Andrikou
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, 47014, Italy
| | - Chiara Bennati
- Department of Onco-Hematology, Santa Maria Delle Croci Hospital, Ravenna, Italy
| | | | | | | | | | - Mirca Valli
- Department of Pathology, Infermi Hospital, Rimini, Italy
| | - Giuseppe Bronte
- Department of Medicina Traslazionale E per la Romagna, University of Ferrara, Ferrara, Italy
- Department of Medical Oncology, University Hospital of Ferrara, Ferrara, Italy
| | - Lucio Crinò
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, 47014, Italy
| | - Angelo Delmonte
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, 47014, Italy
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) “dino Amadori”, Meldola, Italy
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Técher H, Kemiha S, Aobuli X, Kolinjivadi AM. Oncogenic RAS in Cancers from the DNA Replication Stress and Senescence Perspective. Cancers (Basel) 2024; 16:3993. [PMID: 39682179 DOI: 10.3390/cancers16233993] [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: 09/11/2024] [Revised: 11/15/2024] [Accepted: 11/24/2024] [Indexed: 12/18/2024] Open
Abstract
Rat Sarcoma (RAS)-driven cancers have been one of the main foci in the field of cancer science for over four decades. Despite significant improvement in understanding the biology of RAS oncogene, the method to target RAS-mutated cancers is still unclear. In recent years, the role for RAS beyond its hyperproliferation has been extensively documented. In this review, we systematically address and dwell on the details of the mechanisms of RAS oncogene-mediated alteration in the DNA replication and DNA damage response (DDR) pathways, focusing on lung cancers. We further extend this molecular connection towards cytosolic DNA accumulation, innate immune activation and senescence in RAS-addicted cancers. At the end, we briefly speculate on the potential strategies for targeting RAS mutated lung cancers, considering various approaches targeting DNA replication, DNA repair and the cGAS-STING pro-inflammatory pathway. These new lines of therapy, especially when used in combinations, may enhance treatment efficacy and overcome the challenges associated with these mutations.
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Affiliation(s)
- Hervé Técher
- Université Côte d'Azur, Institute for Research on Cancer and Aging of Nice-IRCAN, CNRS, INSERM, 06100 Nice, France
| | - Samira Kemiha
- Université Côte d'Azur, Institute for Research on Cancer and Aging of Nice-IRCAN, CNRS, INSERM, 06100 Nice, France
| | - Xieraili Aobuli
- Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Arun Mouli Kolinjivadi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
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Yu T, Lok BH. Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer. Cancers (Basel) 2024; 16:3438. [PMID: 39456533 PMCID: PMC11506711 DOI: 10.3390/cancers16203438] [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: 08/29/2024] [Revised: 10/04/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance.
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Affiliation(s)
- Tony Yu
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
| | - Benjamin H. Lok
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON M5G 2M9, Canada
- Department of Radiation Oncology, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen’s Park Crescent, Toronto, ON M5S 3H2, Canada
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Taniguchi H, Chakraborty S, Takahashi N, Banerjee A, Caeser R, Zhan YA, Tischfield SE, Chow A, Nguyen EM, Villalonga ÁQ, Manoj P, Shah NS, Rosario S, Hayatt O, Qu R, de Stanchina E, Chan J, Mukae H, Thomas A, Rudin CM, Sen T. ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer. SCIENCE ADVANCES 2024; 10:eado4618. [PMID: 39331709 PMCID: PMC11430494 DOI: 10.1126/sciadv.ado4618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 08/23/2024] [Indexed: 09/29/2024]
Abstract
Patients with small-cell lung cancer (SCLC) have poor prognosis and typically experience only transient benefits from combined immune checkpoint blockade (ICB) and chemotherapy. Here, we show that inhibition of ataxia telangiectasia and rad3 related (ATR), the primary replication stress response activator, induces DNA damage-mediated micronuclei formation in SCLC models. ATR inhibition in SCLC activates the stimulator of interferon genes (STING)-mediated interferon signaling, recruits T cells, and augments the antitumor immune response of programmed death-ligand 1 (PD-L1) blockade in mouse models. We demonstrate that combined ATR and PD-L1 inhibition causes improved antitumor response than PD-L1 alone as the second-line treatment in SCLC. This study shows that targeting ATR up-regulates major histocompatibility class I expression in preclinical models and SCLC clinical samples collected from a first-in-class clinical trial of ATR inhibitor, berzosertib, with topotecan in patients with relapsed SCLC. Targeting ATR represents a transformative vulnerability of SCLC and is a complementary strategy to induce STING-interferon signaling-mediated immunogenicity in SCLC.
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Affiliation(s)
- Hirokazu Taniguchi
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Subhamoy Chakraborty
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nobuyuki Takahashi
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Avisek Banerjee
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rebecca Caeser
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yingqian A. Zhan
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sam E. Tischfield
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrew Chow
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Evelyn M. Nguyen
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Álvaro Quintanal Villalonga
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Parvathy Manoj
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nisargbhai S. Shah
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Samantha Rosario
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Omar Hayatt
- Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rui Qu
- Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joseph Chan
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Program for Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hiroshi Mukae
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Anish Thomas
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Charles M. Rudin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Triparna Sen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Bzura A, Spicer JB, Dulloo S, Yap TA, Fennell DA. Targeting DNA Damage Response Deficiency in Thoracic Cancers. Drugs 2024; 84:1025-1033. [PMID: 39001941 DOI: 10.1007/s40265-024-02066-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2024] [Indexed: 07/15/2024]
Abstract
Thoracic cancers comprise non-small cell lung cancers (NSCLCs), small cell lung cancers (SCLCs) and malignant pleural mesotheliomas (MPM). Collectively, they account for the highest rate of death from malignancy worldwide. Genomic instability is a universal feature of cancer, which fuels mutations and tumour evolution. Deficiencies in DNA damage response (DDR) genes amplify genomic instability. Homologous recombination deficiency (HRD), resulting from BRCA1/BRCA2 inactivation, is exploited for therapeutic synthetic lethality with poly-ADP ribose polymerase (PARP) inhibitors in breast and ovarian cancers, as well as in prostate and pancreatic cancers. However, DDR deficiency and its therapeutic implications are less well established in thoracic cancers. Emerging evidence suggests that a subset of thoracic cancers may harbour DDR deficiency and may, thus, be effectively targeted with DDR agents. Here, we review the current evidence surrounding DDR in thoracic cancers and discuss the challenges and promise for achieving clinical benefit with such therapeutics.
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Affiliation(s)
- Aleksandra Bzura
- University of Leicester, NIHR Biomedical Research Centre and Robert Kilpatrick Clinical Sciences Building, Leicester, UK
| | - Jake B Spicer
- University of Leicester, NIHR Biomedical Research Centre and Robert Kilpatrick Clinical Sciences Building, Leicester, UK
| | - Sean Dulloo
- University of Leicester, NIHR Biomedical Research Centre and Robert Kilpatrick Clinical Sciences Building, Leicester, UK
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Timothy A Yap
- University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dean A Fennell
- University of Leicester, NIHR Biomedical Research Centre and Robert Kilpatrick Clinical Sciences Building, Leicester, UK.
- University Hospitals of Leicester NHS Trust, Leicester, UK.
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Zeng Q, Chen H, Wang Z, Guo Y, Wu Y, Hu Y, Liang P, Zheng Z, Liang T, Zhai D, Guo Y, Liu L, Shen C, Jiang C, Shen Q, Yi Y, Liu Q. Carrier-free cryptotanshinone-peptide conjugates self-assembled nanoparticles: An efficient and low-risk strategy for acne vulgaris. Asian J Pharm Sci 2024; 19:100946. [PMID: 39246508 PMCID: PMC11374989 DOI: 10.1016/j.ajps.2024.100946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/29/2024] [Accepted: 04/14/2024] [Indexed: 09/10/2024] Open
Abstract
Acne vulgaris ranks as the second most prevalent dermatological condition worldwide, and there are still insufficient safe and reliable drugs to treat it. Cryptotanshinone (CTS), a bioactive compound derived from traditional Chinese medicine Salvia miltiorrhiza, has shown promise for treating acne vulgaris due to its broad-spectrum antimicrobial and significant anti-inflammatory properties. Nevertheless, its local application is hindered by its low solubility and poor skin permeability. To overcome these challenges, a carrier-free pure drug self-assembled nanosystem is employed, which can specifically modify drug molecules based on the disease type and microenvironment, offering a potential for more effective treatment. We designed and synthesized three distinct structures of cationic CTS-peptide conjugates, creating self-assembled nanoparticles. This study has explored their self-assembly behavior, skin permeation, cellular uptake, and both in vitro and in vivo anti-acne effects. Molecular dynamics simulations revealed these nanoparticles form through intermolecular hydrogen bonding and π-π stacking interactions. Notably, self-assembled nanoparticles demonstrated enhanced bioavailability with higher skin permeation and cellular uptake rates. Furthermore, the nanoparticles exhibited superior anti-acne effects compared to the parent drug, attributed to heightened antimicrobial activity and significant downregulation of the MAPK/NF-κB pathway, leading to reduced expression of pro-inflammatory factors including TNF-α, IL-1β and IL-8. In summary, the carrier-free self-assembled nanoparticles based on CTS-peptide conjugate effectively address the issue of poor skin bioavailability, offering a promising new approach for acne treatment.
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Affiliation(s)
- Quanfu Zeng
- Dermatology Hospital, Southern Medical University, Guangzhou 510091, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Hongkai Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zhuxian Wang
- Dermatology Hospital, Southern Medical University, Guangzhou 510091, China
| | - Yinglin Guo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yufan Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yi Hu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Peiyi Liang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zeying Zheng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Tao Liang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Dan Zhai
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yaling Guo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Li Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Chunyan Shen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Cuiping Jiang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Qun Shen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yankui Yi
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Qiang Liu
- Dermatology Hospital, Southern Medical University, Guangzhou 510091, China
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Doerr F, Stange S, Salamon S, Grapatsas K, Baldes N, Michel M, Menghesha H, Schlachtenberger G, Heldwein MB, Hagmeyer L, Wolf J, Roessner ED, Wahlers T, Schuler M, Hekmat K, Bölükbas S. Closing the RCT Gap-A Large Meta-Analysis on the Role of Surgery in Stage I-III Small Cell Lung Cancer Patients. Cancers (Basel) 2024; 16:2078. [PMID: 38893197 PMCID: PMC11171341 DOI: 10.3390/cancers16112078] [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: 03/31/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
INTRODUCTION Despite clear guideline recommendations, surgery is not consistently carried out as part of multimodal therapy in stage I small cell lung cancer (SCLC) patients. The role of surgery in stages II and III is even more controversial. In the absence of current randomized control trials (RCT), we performed a meta-analysis comparing surgery versus non-surgical treatment in stage I to III SCLC patients. METHODS A systematic review of the literature was conducted on 1 July 2023, focusing on studies pertaining to the impact of surgery on small cell lung cancer (SCLC). These studies were evaluated using the ROBINS-I tool. Statistical analyses, including I² tests, Q-statistics, DerSimonian-Laird tests, and Egger regression, were performed to assess the data. In addition, 5-year survival rates were analyzed. The meta-analysis was conducted according to PRISMA standards. RESULTS Among the 6826 records identified, 10 original studies encompassing a collective cohort of 95,323 patients were incorporated into this meta-analysis. Heterogeneity was observed across the included studies, with no discernible indication of publication bias. Analysis of patient characteristics revealed no significant differences between the two groups (p-value > 0.05). The 5-year survival rates in a combined analysis of patients in stages I-III were 39.6 ± 15.3% for the 'surgery group' and 16.7 ± 12.7% for the 'non-surgery group' (p-value < 0.0001). SCLC patients in stages II and III treated outside the guideline with surgery had a significantly better 5-year survival compared to non-surgery controls (36.3 ± 20.2% vs. 20.2 ± 17.0%; p-value = 0.043). CONCLUSIONS In the absence of current RCTs, this meta-analysis provides robust suggestions that surgery might significantly improve survival in all SCLC stages. Non-surgical therapy could lead to a shortening of life. The feasibility of surgery in non-metastatic SCLC should always be evaluated as part of a multimodal treatment.
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Affiliation(s)
- Fabian Doerr
- Department of Thoracic Surgery, West German Cancer Center, University Medical Center Essen-Ruhrlandklinik, University Duisburg-Essen, 45239 Essen, Germany
| | - Sebastian Stange
- Department of Thoracic Surgery, Regiomed-Klinikum Coburg GmbH, 96450 Coburg, Germany
| | | | - Konstantinos Grapatsas
- Department of Thoracic Surgery, West German Cancer Center, University Medical Center Essen-Ruhrlandklinik, University Duisburg-Essen, 45239 Essen, Germany
| | - Natalie Baldes
- Department of Thoracic Surgery, West German Cancer Center, University Medical Center Essen-Ruhrlandklinik, University Duisburg-Essen, 45239 Essen, Germany
| | - Maximilian Michel
- Institute of Zoology, Faculty of Mathematics and Natural Sciences, University of Cologne, 50674 Cologne, Germany
| | - Hruy Menghesha
- Department of Thoracic Surgery, Helios Clinic Bonn/Rhein-Sieg, 53123 Bonn, Germany
- Division of Thoracic Surgery, Department of General, Thoracic and Vascular Surgery, Bonn University Hospital, 53127 Bonn, Germany
| | - Georg Schlachtenberger
- Department of Cardiothoracic Surgery, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany
| | - Matthias B. Heldwein
- Department of Cardiothoracic Surgery, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany
| | - Lars Hagmeyer
- Clinic for Pneumology and Allergology, Bethanien Hospital GmbH, 42699 Solingen, Germany
| | - Jürgen Wolf
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
| | - Eric D. Roessner
- Interdisciplinary Thoracic Center, Division of Thoracic Surgery, University Hospital of Mainz, University of Mainz, 55131 Mainz, Germany
| | - Thorsten Wahlers
- Department of Cardiothoracic Surgery, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Medical Center Essen, University Duisburg-Essen, 45147 Essen, Germany
- National Center for Tumor Diseases (NCT) West, Campus Essen, 45147 Essen, Germany
| | - Khosro Hekmat
- Department of Cardiothoracic Surgery, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany
| | - Servet Bölükbas
- Department of Thoracic Surgery, West German Cancer Center, University Medical Center Essen-Ruhrlandklinik, University Duisburg-Essen, 45239 Essen, Germany
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Chao Y, Chen Y, Zheng W, Demanelis K, Liu Y, Connelly JA, Wang H, Li S, Wang QJ. Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer. Oncogene 2024; 43:789-803. [PMID: 38273024 PMCID: PMC11556418 DOI: 10.1038/s41388-024-02939-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 01/27/2024]
Abstract
WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.
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Affiliation(s)
- Yapeng Chao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yuzhou Chen
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Wenxiao Zheng
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kathryn Demanelis
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, USA
| | - Yu Liu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jaclyn A Connelly
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Hong Wang
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Song Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Qiming Jane Wang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Oser MG, MacPherson D, Oliver TG, Sage J, Park KS. Genetically-engineered mouse models of small cell lung cancer: the next generation. Oncogene 2024; 43:457-469. [PMID: 38191672 PMCID: PMC11180418 DOI: 10.1038/s41388-023-02929-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/10/2024]
Abstract
Small cell lung cancer (SCLC) remains the most fatal form of lung cancer, with patients in dire need of new and effective therapeutic approaches. Modeling SCLC in an immunocompetent host is essential for understanding SCLC pathogenesis and ultimately discovering and testing new experimental therapeutic strategies. Human SCLC is characterized by near universal genetic loss of the RB1 and TP53 tumor suppressor genes. Twenty years ago, the first genetically-engineered mouse model (GEMM) of SCLC was generated using conditional deletion of both Rb1 and Trp53 in the lungs of adult mice. Since then, several other GEMMs of SCLC have been developed coupling genomic alterations found in human SCLC with Rb1 and Trp53 deletion. Here we summarize how GEMMs of SCLC have contributed significantly to our understanding of the disease in the past two decades. We also review recent advances in modeling SCLC in mice that allow investigators to bypass limitations of the previous generation of GEMMs while studying new genes of interest in SCLC. In particular, CRISPR/Cas9-mediated somatic gene editing can accelerate how new genes of interest are functionally interrogated in SCLC tumorigenesis. Notably, the development of allograft models and precancerous precursor models from SCLC GEMMs provides complementary approaches to GEMMs to study tumor cell-immune microenvironment interactions and test new therapeutic strategies to enhance response to immunotherapy. Ultimately, the new generation of SCLC models can accelerate research and help develop new therapeutic strategies for SCLC.
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Affiliation(s)
- Matthew G Oser
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| | - David MacPherson
- Division of Human Biology, Fred Hutch Cancer Center, Seattle, WA, 98109, USA
| | - Trudy G Oliver
- Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, 27708, USA
| | - Julien Sage
- Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA
- Department of Genetics, Stanford University, Stanford, CA, 94305, USA
| | - Kwon-Sik Park
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22903, USA.
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10
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Wang Q, Chao Y, Chen Y, Zheng W, Demanelis K, Liu Y, Connelly J, Wang H. Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer. RESEARCH SQUARE 2023:rs.3.rs-3564450. [PMID: 37987002 PMCID: PMC10659531 DOI: 10.21203/rs.3.rs-3564450/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC/NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.
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Affiliation(s)
| | | | | | | | | | - Yu Liu
- University of Pittsburgh Cancer Institute
| | | | - Hong Wang
- University of Pittsburgh Cancer Institute
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11
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Thapa R, Afzal O, Bhat AA, Goyal A, Alfawaz Altamimi AS, Almalki WH, Alzarea SI, Kazmi I, Singh SK, Dua K, Thangavelu L, Gupta G. New horizons in lung cancer management through ATR/CHK1 pathway modulation. Future Med Chem 2023; 15:1807-1818. [PMID: 37877252 DOI: 10.4155/fmc-2023-0164] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Molecular profiling has contributed to a new classification of lung cancer, driving advancements in research and therapy. The ataxia telangiectasia and rad3/checkpoint kinase 1 (ATR/CHK1) pathway plays a crucial role in maintaining genomic stability, and its activation has been linked to the development of lung cancer, drug resistance and poor prognosis. Clinical and preclinical studies have demonstrated promising results in targeting this pathway. ATR and CHK1 are proteins that collaborate to repair DNA damage caused by radiation or chemotherapy. ATR/CHK1 inhibitors are currently under investigation in preclinical and clinical trials. This article explores the ATR/CHK1 pathway and its potential for treating lung cancer.
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Affiliation(s)
- Riya Thapa
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
| | - Asif Ahmad Bhat
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, U.P., India
| | | | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, India
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology, Sydney, Ultimo, NSW, 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology, Sydney, Ultimo, NSW, 2007, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology, Sydney, Ultimo-NSW, 2007, Australia
| | - Lakshmi Thangavelu
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical & Technical Sciences, Saveetha University, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
- School of Pharmacy, Graphic Era Hill University Dehradun, 248007, India
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12
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Jiang F, Huang X, Ling L, Tang S, Zhou H, Cai X, Wang Y. Long Noncoding RNA ZBED5-AS1 Facilitates Tumor Progression and Metastasis in Lung Adenocarcinoma via ZNF146/ATR/Chk1 Axis. Int J Mol Sci 2023; 24:13925. [PMID: 37762228 PMCID: PMC10530271 DOI: 10.3390/ijms241813925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis, including lung adenocarcinoma (LUAD). However, the functional and regulatory mechanisms of lncRNAs in LUAD remain poorly understood. In this study, we investigated the role of lncRNA ZBED5-AS1 in LUAD. We found that ZBED5-AS1 was upregulated in LUAD specimens and overexpressed in LUAD cell lines. ZBED5-AS1 promoted LUAD cell proliferation, migration, and invasion in vitro and promoted LUAD cell growth in vivo. ZBED5-AS1 promoted ZNF146 expression, activating the ATR/Chk1 pathway and leading to LUAD progression. We observed that exosomes from LUAD cells have a higher expression of ZBED5-AS1 compared with exosomes from the normal cell line BEAS-2B. Coculture experiments with exosomes showed that ZBED5-AS1 expression was downregulated after coculture with Si-ZBED5-AS1 exosomes, and coculture with exosomes with low ZBED5-AS1 expression inhibited proliferation and invasion of LUAD cells. Our results indicate that ZBED5-AS1 functions as an oncogenic factor in LUAD cells by targeting the ZNF146/ATR/Chk1 axis.
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Affiliation(s)
- Feng Jiang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; (F.J.)
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou 325015, China
| | - Xiaolu Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; (F.J.)
| | - Liqun Ling
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; (F.J.)
| | - Shiyi Tang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; (F.J.)
| | - Huixin Zhou
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; (F.J.)
| | - Xueding Cai
- Department of Respiration, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China
| | - Yumin Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; (F.J.)
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou 325015, China
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13
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Li L, Wang L, Liu D, Zhao Y. BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1. Cell Death Discov 2023; 9:313. [PMID: 37626049 PMCID: PMC10457387 DOI: 10.1038/s41420-023-01611-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 08/10/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Checkpoint kinase 1 (CHK1), a key effector in the cellular response to DNA lesions, is a crucial component of all cell cycle checkpoints. Recent reports have revealed that CHK1 is highly expressed in numerous cancer types in the clinical settings. However, the mechanisms underlying the regulation of CHK1 expression in tumor cells remain unclear. Here, we report that CHK1 is negatively regulated by the bromodomain-containing protein 7 (BRD7). Specifically, BRD7 silencing increased CHK1 (but not CHK2) expression at both mRNA and protein levels, in a p53-independent manner in multiple tumor cell lines. Furthermore, BRD7 silencing stabilized CHK1 via reducing its ubiquitination. Mechanistically, BRD7 knockdown not only increased the levels of USP1, a deubiquitinase for CHK1, but also promoted the interaction between CHK1 and USP1, subsequently enhancing the de-ubiquitination of CHK1. USP1 knockdown abrogated BRD7 silencing-induced CHK1 induction. Biologically, the increased expression of CHK1 in tumor cells caused by BRD7 silencing significantly increased cell sensitivity to CHK1 inhibitors by enhancing tumor cell apoptosis, and this effect was reversed by the simultaneous knockdown of CHK1 or USP1. Taken together, our findings suggest that BRD7 is a potential genetic or drug target that may help to improve the efficacy of chemotherapeutic drugs targeting CHK1 in combinatorial therapy.
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Affiliation(s)
- Lemin Li
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Linchen Wang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Dian Liu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
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14
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Parisi A, Rossi F, De Filippis C, Paoloni F, Felicetti C, Mammarella A, Pecci F, Lupi A, Berardi R. Current Evidence and Future Perspectives about the Role of PARP Inhibitors in the Treatment of Thoracic Cancers. Onco Targets Ther 2023; 16:585-613. [PMID: 37485307 PMCID: PMC10362869 DOI: 10.2147/ott.s272563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 07/09/2023] [Indexed: 07/25/2023] Open
Abstract
In recent years, poly (ADP-ribose) polymerase (PARP) inhibition has become a promising therapeutic option for several tumors, especially for those harboring a BRCA 1-2 mutation or a deficit in the homologous recombination repair (HRR) pathway. Nevertheless, to date, PARP inhibitors are still not largely used for thoracic malignancies neither as a single agent nor in combination with other treatments. Recently, a deeper understanding of HRR mechanisms, alongside the development of new targeted and immunotherapy agents, particularly against HRR-deficient tumors, traced the path to new treatment strategies for many tumor types including lung cancer and malignant pleural mesothelioma. The aim of this review is to sum up the current knowledge about cancer-DNA damage response pathways inhibition and to update the status of recent clinical trials investigating the use of PARP inhibitors, either as monotherapy or in combination with other agents for the treatment of thoracic malignancies. We will also briefly discuss available evidence on Poly(ADP-Ribose) Glycohydrolase (PARG) inhibitors, a novel promising therapeutic option in oncology.
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Affiliation(s)
- Alessandro Parisi
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Francesca Rossi
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Chiara De Filippis
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Francesco Paoloni
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Cristiano Felicetti
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Alex Mammarella
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Federica Pecci
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Alessio Lupi
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
| | - Rossana Berardi
- Department of Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria delle Marche, Ancona, 60126, Italy
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15
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Zhang C, Zhang C, Wang K, Wang H. Orchestrating smart therapeutics to achieve optimal treatment in small cell lung cancer: recent progress and future directions. J Transl Med 2023; 21:468. [PMID: 37452395 PMCID: PMC10349514 DOI: 10.1186/s12967-023-04338-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 07/09/2023] [Indexed: 07/18/2023] Open
Abstract
Small cell lung cancer (SCLC) is a recalcitrant malignancy with elusive mechanism of pathogenesis and dismal prognosis. Over the past decades, platinum-based chemotherapy has been the backbone treatment for SCLC. However, subsequent chemoresistance after initial effectiveness urges researchers to explore novel therapeutic targets of SCLC. Recent years have witnessed significant improvements in targeted therapy in SCLC. New molecular candidates such as Ataxia telangiectasia and RAD3-related protein (ATR), WEE1, checkpoint kinase 1 (CHK1) and poly-ADP-ribose polymerase (PARP) have shown promising therapeutic utility in SCLC. While immune checkpoint inhibitor (ICI) has emerged as an indispensable treatment modality for SCLC, approaches to boost efficacy and reduce toxicity as well as selection of reliable biomarkers for ICI in SCLC have remained elusive and warrants our further investigation. Given the increasing importance of precision medicine in SCLC, optimal subtyping of SCLC using multi-omics have gradually applied into clinical practice, which may identify more drug targets and better tailor treatment strategies to each individual patient. The present review summarizes recent progress and future directions in SCLC. In addition to the emerging new therapeutics, we also focus on the establishment of predictive model for early detection of SCLC. More importantly, we also propose a multi-dimensional model in the prognosis of SCLC to ultimately attain the goal of accurate treatment of SCLC.
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Affiliation(s)
- Chenyue Zhang
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, China
| | - Chenxing Zhang
- Department of Nephrology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Wang
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Haiyong Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Number 440, Ji Yan Road, Jinan, China.
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16
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Xie D, Jiang B, Wang S, Wang Q, Wu G. The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer. Front Cell Dev Biol 2023; 11:1200466. [PMID: 37305685 PMCID: PMC10248030 DOI: 10.3389/fcell.2023.1200466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/18/2023] [Indexed: 06/13/2023] Open
Abstract
Urologic cancers such as kidney, bladder, prostate, and uroepithelial cancers have recently become a considerable global health burden, and the response to immunotherapy is limited due to immune escape and immune resistance. Therefore, it is crucial to find appropriate and effective combination therapies to improve the sensitivity of patients to immunotherapy. DNA damage repair inhibitors can enhance the immunogenicity of tumor cells by increasing tumor mutational burden and neoantigen expression, activating immune-related signaling pathways, regulating PD-L1 expression, and reversing the immunosuppressive tumor microenvironment to activate the immune system and enhance the efficacy of immunotherapy. Based on promising experimental results from preclinical studies, many clinical trials combining DNA damage repair inhibitors (e.g., PARP inhibitors and ATR inhibitors) with immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) are underway in patients with urologic cancers. Results from several clinical trials have shown that the combination of DNA damage repair inhibitors with immune checkpoint inhibitors can improve objective rates, progression-free survival, and overall survival (OS) in patients with urologic tumors, especially in patients with defective DNA damage repair genes or a high mutational load. In this review, we present the results of preclinical and clinical trials of different DNA damage repair inhibitors in combination with immune checkpoint inhibitors in urologic cancers and summarize the potential mechanism of action of the combination therapy. Finally, we also discuss the challenges of dose toxicity, biomarker selection, drug tolerance, drug interactions in the treatment of urologic tumors with this combination therapy and look into the future direction of this combination therapy.
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Affiliation(s)
| | | | | | - Qifei Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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17
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Khadela A, Postwala H, Rana D, Dave H, Ranch K, Boddu SHS. A review of recent advances in the novel therapeutic targets and immunotherapy for lung cancer. Med Oncol 2023; 40:152. [PMID: 37071269 DOI: 10.1007/s12032-023-02005-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 03/22/2023] [Indexed: 04/19/2023]
Abstract
Lung cancer is amongst the most pervasive malignancies having high mortality rates. It is broadly grouped into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The concept of personalized medicine has overshadowed the conventional chemotherapy given to all patients with lung cancer. The targeted therapy is given to a particular population having specific mutations to help in the better management of lung cancer. The targeting pathways for NSCLC include the epidermal growth factor receptor, vascular endothelial growth factor receptor, MET (Mesenchymal epithelial transition factor) oncogene, Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK). SCLC targeting pathway includes Poly (ADP-ribose) polymerases (PARP) inhibitors, checkpoint kinase 1 (CHK 1) pathway, WEE1 pathway, Ataxia Telangiectasia and Rad3-related (ATR)/Ataxia telangiectasia mutated (ATM), and Delta-like canonical Notch ligand 3 (DLL-Immune checkpoint inhibitors like programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors and Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade are also utilized in the management of lung cancer. Many of the targeted therapies are still under development and require clinical trials to establish their safety and efficacy. This review summarizes the mechanism of molecular targets and immune-mediated targets, recently approved drugs, and their clinical trials for lung cancer.
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Affiliation(s)
- Avinash Khadela
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India.
| | - Humzah Postwala
- Pharm.D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Deval Rana
- Pharm.D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Hetvi Dave
- Pharm.D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Ketan Ranch
- Department of Pharmaceutics and Pharm. Technology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Sai H S Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P.O. Box 346, Ajman, United Arab Emirates
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18
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Zhang C, Wang H. Accurate treatment of small cell lung cancer: Current progress, new challenges and expectations. Biochim Biophys Acta Rev Cancer 2022; 1877:188798. [PMID: 36096336 DOI: 10.1016/j.bbcan.2022.188798] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 09/05/2022] [Indexed: 11/28/2022]
Abstract
Small cell lung cancer (SCLC) is a deadly disease with poor prognosis. Fast growing speed, inclination to metastasis, enrichment in cancer stem cells altogether constitute its aggressive nature. In stark contrast to non-small cell lung cancer (NSCLC) that strides vigorously on the road to precision oncology, SCLC has been on the embryonic path to achieve effective personalized treatments. The survival of patients with SCLC have not been improved greatly, which could be possibly due to our inadequate understanding of genetic alterations of SCLC. Recently, encouraging effects have been observed in patients with SCLC undergoing immunotherapy. However, exciting results have only been observed in a small fraction of patients with SCLC, warranting biomarkers predictive of responses as well as novel therapeutic strategies. In addition, SCLC has previously been viewed to be homogeneous. However, perspectives have been changed thanks to the advances in sequencing techniques and platforms, which unfolds the complex heterogeneity of SCLC both genetically and non-genetically, rendering the treatment of SCLC a further step forward into the precision era. To outline the road of SCLC towards precision oncology, we summarize the progresses and achievements made in precision treatment in SCLC in genomic, transcriptomic, epigenetic, proteomic and metabolic dimensions. Moreover, we conclude relevant therapeutic vulnerabilities in SCLC. Clinically tested drugs and clinical trials have also been demonstrated. Ultimately, we look into the opportunities and challenges ahead to advance the individualized treatment in pursuit of improved survival for patients with SCLC.
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Affiliation(s)
- Chenyue Zhang
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, China
| | - Haiyong Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
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19
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Kanemura H, Hayashi H, Tomida S, Tanizaki J, Suzuki S, Kawanaka Y, Tsuya A, Fukuda Y, Kaneda H, Kudo K, Takahama T, Imai R, Haratani K, Chiba Y, Otani T, Ito A, Sakai K, Nishio K, Nakagawa K. The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC. JTO Clin Res Rep 2022; 3:100373. [PMID: 35941997 PMCID: PMC9356091 DOI: 10.1016/j.jtocrr.2022.100373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/06/2022] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
- Hiroaki Kanemura
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
- Corresponding author. Address for correspondence: Hidetoshi Hayashi, MD, PhD, Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
| | - Shuta Tomida
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Junko Tanizaki
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
- Department of Medical Oncology, Kishiwada City Hospital, Osaka, Japan
| | - Shinichiro Suzuki
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
- Department of Medical Oncology, Kishiwada City Hospital, Osaka, Japan
| | - Yusuke Kawanaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
- Department of Medical Oncology, Kishiwada City Hospital, Osaka, Japan
| | - Asuka Tsuya
- Department of Medical Oncology, Izumi City General Hospital, Osaka, Japan
| | - Yasushi Fukuda
- Department of Respiratory Medicine, Kurashiki Central Hospital, Okayama, Japan
| | - Hiroyasu Kaneda
- Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Keita Kudo
- Department of Thoracic Medical Oncology, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan
| | - Takayuki Takahama
- Department of Medical Oncology, Kindai University Nara Hospital, Nara, Japan
| | - Ryosuke Imai
- Department of Pulmonary Medicine, Thoracic Center, St. Luke’s International Hospital, Tokyo, Japan
| | - Koji Haratani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Hospital, Osaka, Japan
| | - Tomoyuki Otani
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Akihiko Ito
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
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20
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Stage I and II Small-Cell Lung Cancer-New Challenge for Surgery. Lung 2022; 200:505-512. [PMID: 35768664 PMCID: PMC9360162 DOI: 10.1007/s00408-022-00549-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 06/03/2022] [Indexed: 12/24/2022]
Abstract
Purpose The recommended treatment for small-cell lung cancer (SCLC) currently is surgery in stage I disease. We wondered about stage II SCLC and present a meta-analysis on mean-survival of patients that underwent surgery for stage I and II compared to controls. Methods A systematic literature search was performed on December 01st 2021 in Medline, Embase and Cochrane Library. We considered studies published on the effect of surgery in SCLC since 2004 and assessed them using ROBINS-I. We preformed I2-tests, Q-statistics, DerSimonian-Laird tests and Egger-regression. The meta-analysis was conducted according to PRISMA. Results Out of 6826 records, seven studies with a total of 11,241 patients (‘surgery group’: 3911 patients; ‘non-surgery group’: 7330; treatment period: 1984–2015) were included. Heterogeneity between the studies was revealed in absence of any publication bias. Patient characteristics did not differ between the groups (p-value > 0.05). The mean-survival in an analysis of patients in stage I was 36.7 ± 10.8 months for the ‘surgery group’ and 20.3 ± 5.7 months for the ‘non-surgery group’ (p-value = 0.0084). A combined analysis of patients in stage I and II revealed a mean-survival of 32.0 ± 16.7 months for the ‘surgery group’ and 19.1 ± 6.1 months for the ‘non-surgery group’ (p-value = 0.0391). In a separate analysis of stage II, we were able to demonstrate a significant survival benefit after surgery (21.4 ± 3.6 versus 16.2 ± 3.9 months; p-value = 0.0493). Conclusion Our meta-analysis shows a significant survival benefit after surgery not only in the recommended stage I but also in stage II SCLC. Our data suggests that both stages should be considered for surgery of early SCLC.
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21
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Wang WZ, Shulman A, Amann JM, Carbone DP, Tsichlis PN. Small cell lung cancer: Subtypes and therapeutic implications. Semin Cancer Biol 2022; 86:543-554. [DOI: 10.1016/j.semcancer.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/23/2022] [Accepted: 04/04/2022] [Indexed: 12/20/2022]
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22
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Abstract
Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold lung cancer subtype. Historically viewed in the laboratory and clinic as a single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members and lineage-related transcription factors ASCL1, NEUROD1, and POU2F3 (and, in some studies, YAP1) define unique molecular states that have been associated with distinct responses to a variety of therapies. However, SCLC tumors exhibit a high degree of intratumoral heterogeneity, with recent studies suggesting the existence of tumor cell plasticity and phenotypic switching between subtype states. While SCLC plasticity is correlated with, and likely drives, therapeutic resistance, the mechanisms underlying this plasticity are still largely unknown. Subtype states are also associated with immune-related gene expression, which likely impacts response to immune checkpoint blockade and may reveal novel targets for alternative immunotherapeutic approaches. In this review, we synthesize recent discoveries on the mechanisms of SCLC plasticity and how these processes may impinge on antitumor immunity.
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Affiliation(s)
- Kate D Sutherland
- Australian Cancer Research Foundation (ACRF) Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Abbie S Ireland
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA
| | - Trudy G Oliver
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA
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23
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El Sayed R, El Darsa H. Therapeutic Modalities in Small Cell Lung Cancer: a paradigm shift after decades of quiescence. Expert Opin Pharmacother 2022; 23:583-597. [PMID: 35176957 DOI: 10.1080/14656566.2022.2042515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Small cell lung cancer (SCLC) is known to be the most aggressive of all thoracic malignancies, notoriously known for its very poor prognosis. Platinum based chemotherapy has been the standard of care for decades. Despite years of research, no treatment novelties with significant impact on survival have been achieved until recently. The last few years have witnessed light at the end of the tunnel with immunotherapy proving to improve survival. Nevertheless, responses were not homogeneous in all subgroups, and finding who would best benefit from treatment remains unanswered. Multiple limitations exist, and the quest for optimal biomarkers seemed unfruitful until the discovery of different SCLC phenotypes. AREAS COVERED In this review, the authors briefly discuss SCLC phenotypes and biomarker assays. Then, the authors continue with the main trials of SCLC treatment using chemotherapy, immunotherapy and targeted treatment in the front-line or subsequent line settings. EXPERT OPINION Research has been extensively implemented to better understand the biology of SCLC, and test for the optimal use of immunotherapy in patients with SCLC, as well as to enhance responses via possible combinations. Targeted mechanisms of action have also been attempted; yet no solid proof of efficacy has been established.
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Affiliation(s)
- Rola El Sayed
- Centre Hospitalier de l' Université de Montréal, Université de Montréal, Montréal, Quebec, Ca
| | - Haidar El Darsa
- Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Ca
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24
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Hayashi R, Inomata M. Small cell lung cancer; recent advances of its biology and therapeutic perspective. Respir Investig 2021; 60:197-204. [PMID: 34896039 DOI: 10.1016/j.resinv.2021.10.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/11/2021] [Accepted: 10/30/2021] [Indexed: 12/29/2022]
Abstract
Lung cancer is historically divided into two major categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). While the therapeutic efficacy of NSCLC has improved due to the development of molecular targeted therapy and immune checkpoint inhibitors (ICIs) treatment, there has been very slow progress in the therapeutic advances of SCLC. Since SCLC is a deadly disease with rapid progression and early metastasis and comprises approximately 10% of lung cancer cases, more attention should be given to the therapeutic strategy for SCLC. Most SCLC cases respond to cytotoxic drugs, cisplatin, and etoposide. The objective response rate to the standard regimen is reported to be approximately 70% that is sufficient as standard therapy. However, almost all tumors recur and become refractory to chemotherapy which is the most important problem of this deadly disease. Recently, for the first time in several decades, ICIs have changed the standard therapy for SCLC. It must be emphasized that although ICIs paved the new way for SCLC therapy, more precise and effective therapy for SCLC is desired. Unfortunately, precise molecular mechanisms of SCLC are yet to be understood. Recent elaborate studies on the cell biology of SCLC uncovered several important aspects of molecular mechanisms. Gene profiling of cancer cells can be done using modern technology like next-generation sequencing (NGS). In this minireview, we describe the advances of modern technology in SCLC research and consider future therapeutic strategies based on the molecular mechanisms of SCLC.
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Affiliation(s)
- Ryuji Hayashi
- Clinical Oncology, Toyama University Hospital, Sugitani 2630, Toyama, 930-0194, Japan.
| | - Minehiko Inomata
- 1(st) Department of Internal Medicine, Toyama University Hospital, Sugitani 2630, Toyama, 930-0194, Japan
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25
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Liu H, Li T, Ye X, Lyu J. Identification of Key Biomarkers and Pathways in Small-Cell Lung Cancer Using Biological Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5953386. [PMID: 34712733 PMCID: PMC8548101 DOI: 10.1155/2021/5953386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/25/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Small-cell lung cancer (SCLC) is a major cause of carcinoma-related deaths worldwide. The aim of this study was to identify the key biomarkers and pathways in SCLC using biological analysis. METHODS Key genes involved in the development of SCLC were identified by downloading three datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the GEO2R online analyzer; for the functional annotation and pathway enrichment analysis of genes, Funrich software was used. Construction of protein-to-protein interaction (PPI) networks was accomplished using the Search Tool for the Retrieval of Interacting Genes (STRING), and network visualization and module identification were performed using Cytoscape. RESULTS A total of 268 DEGs were ultimately obtained. The enriched functions and pathways of the upregulated DEGs included cell cycle, mitotic, and DNA replication, and the downregulated DEGs were enriched in epithelial-to-mesenchymal transition, serotonin degradation, and noradrenaline. Analysis of significant modules demonstrated that the upregulated genes are primarily concentrated in functions related to cell cycle and DNA replication. Kaplan-Meier analysis of hub genes revealed that they may promote the carcinogenesis and progression of SCLC. The result of ONCOMINE demonstrated that these 10 hub genes were significantly overexpressed in SCLC compared with normal samples. CONCLUSION Identification of the molecular functions and signaling pathways of participating DEGs can deepen the current understanding of the molecular mechanisms of SCLC. The knowledge gained from this work may contribute to the development of treatment options and improve the prognosis of SCLC in the future.
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Affiliation(s)
- Huanqing Liu
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Tingting Li
- Department of Pharmacy, Xi'an Chest Hospital, Xi'an, Shaanxi, China
| | - Xunda Ye
- Clinical Medicine Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Jun Lyu
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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26
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Hao Z, Sekkath Veedu J. Current Strategies for Extensive Stage Small Cell Lung Cancer Beyond First-line Therapy. Clin Lung Cancer 2021; 23:14-20. [PMID: 34656433 DOI: 10.1016/j.cllc.2021.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/22/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023]
Abstract
Extensive stage small cell lung cancer carries extremely poor prognosis and adding immune checkpoint inhibitor to platinum etoposide combination in first line only improved outcomes modestly. Once disease recurs, treatment response is only transient in nature. Various strategies that are being explored include dual checkpoint blockade, BiTE and CAR-T cell approaches. Immune checkpoint inhibitors are being combined with PARP inhibitors. Other approaches currently being investigated include liposomal irinotecan and combining known active agents for SCLC in relapsed setting such as newly approved lurbinectedin with doxorubicin, paclitaxel, irinotecan or topotecan with ATR inhibitor (Berzosertib). Temozolomide has also been tested in combination with a Parp inhibitor. New antibody or small molecule drug conjugates are being actively investigated, so is a biomarker based approach. Better understanding of small cell lung cancer disease biology via high through-put genomic, proteomic and methylation profiling offer glimpse of hope in our efforts to contain this deadly disease. A table of representative molecular targets under investigation is provided in the end.
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Affiliation(s)
- Zhonglin Hao
- Division of Medical Oncology, Department of Medicine, Markey Cancer Center, College of Medicine, University of Kentucky, Lexington KY.
| | - Janeesh Sekkath Veedu
- Division of Medical Oncology, Department of Medicine, Markey Cancer Center, College of Medicine, University of Kentucky, Lexington KY
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27
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Herzog BH, Devarakonda S, Govindan R. Overcoming Chemotherapy Resistance in SCLC. J Thorac Oncol 2021; 16:2002-2015. [PMID: 34358725 DOI: 10.1016/j.jtho.2021.07.018] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/09/2021] [Accepted: 07/18/2021] [Indexed: 10/20/2022]
Abstract
SCLC is an aggressive form of lung cancer with a very poor prognosis. Although SCLC initially responds very well to platinum-based chemotherapy, it eventually recurs and at recurrence is nearly universally resistant to therapy. In light of the recent advances in understanding regarding the biology of SCLC, we review findings related to SCLC chemotherapy resistance. We discuss the potential clinical implications of recent preclinical discoveries in altered signaling pathways, transcriptional landscapes, metabolic vulnerabilities, and the tumor microenvironment.
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Affiliation(s)
- Brett H Herzog
- Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Alvin J Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri
| | - Siddhartha Devarakonda
- Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Alvin J Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri
| | - Ramaswamy Govindan
- Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Alvin J Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.
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28
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Repositioning PARP inhibitors in the treatment of thoracic malignancies. Cancer Treat Rev 2021; 99:102256. [PMID: 34261032 DOI: 10.1016/j.ctrv.2021.102256] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 12/17/2022]
Abstract
The evaluation of the homologous recombination repair (HRR) status is emerging as a predictive tumor agnostic biomarker for poly (ADP-ribose) polymerase (PARP) inhibition across different tumor types and testing for HRR-signature is currently a developing area with promising therapeutic implications. Treatment with PARP inhibitors (PARPi) either as single agent or in combination with chemotherapy have shown so far limited activity in patients with thoracic malignancies. A deeper understanding of the biological background underlying HRR-deficient tumors, along with the recent advent of new effective targeted and immunotherapeutic agents, prompted the design of a new generation of clinical trials investigating novel PARPi-combinations in patients with lung cancer as well as malignant pleural mesothelioma. In this review we briefly summarize the biological basis of the DNA damage response pathway inhibition and provide an updated and detailed overview of clinical trials testing different PARPi-combinations strategies in patients with thoracic malignancies.
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29
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Jin R, Peng L, Shou J, Wang J, Jin Y, Liang F, Zhao J, Wu M, Li Q, Zhang B, Wu X, Lan F, Xia L, Yan J, Shao Y, Stebbing J, Shen H, Li W, Xia Y. EGFR-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes. Front Oncol 2021; 11:680804. [PMID: 34195081 PMCID: PMC8236808 DOI: 10.3389/fonc.2021.680804] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/26/2021] [Indexed: 12/15/2022] Open
Abstract
Background The therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy. Material and Methods We consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed. Results In total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P<0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS. Conclusions EGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs.
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Affiliation(s)
- Rui Jin
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ling Peng
- Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Hangzhou, China.,Department of Radiotherapy, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiawei Shou
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jin Wang
- Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
| | - Yin Jin
- Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
| | - Fei Liang
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Zhao
- Department of Medical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Mengmeng Wu
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON, Canada
| | - Qin Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Zhang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoying Wu
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON, Canada
| | - Fen Lan
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lixia Xia
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Junrong Yan
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON, Canada
| | - Yang Shao
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON, Canada
| | - Justin Stebbing
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Huahao Shen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yang Xia
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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30
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Norton JP, Augert A, Eastwood E, Basom R, Rudin CM, MacPherson D. Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas. Genes Dev 2021; 35:870-887. [PMID: 34016692 PMCID: PMC8168556 DOI: 10.1101/gad.348316.121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022]
Abstract
Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcinoma treated ex vivo or in vivo. A subset of PDX models were exceptionally sensitive to neddylation inhibition. Neddylation inhibition suppressed expression of major regulators of neuroendocrine cell state such as INSM1 and ASCL1, which a subset of SCLC rely upon for cell proliferation and survival. To identify potential mechanisms of resistance to neddylation inhibition, we performed a genome-scale CRISPR/Cas9 suppressor screen. Deletion of components of the COP9 signalosome strongly mitigated the effects of neddylation inhibition in small cell carcinoma, including the ability of MLN4924 to suppress neuroendocrine transcriptional program expression. This work identifies neddylation as a regulator of neuroendocrine cell state and potential therapeutic target for small cell carcinomas.
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Affiliation(s)
- Justin P Norton
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.,Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
| | - Arnaud Augert
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.,Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
| | - Emily Eastwood
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.,Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
| | - Ryan Basom
- Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
| | - Charles M Rudin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - David MacPherson
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.,Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.,Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
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31
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Davenport ML, Echols JB, Silva AD, Anderson JC, Owens P, Yates C, Wei Q, Harada S, Hurst DR, Edmonds MD. miR-31 Displays Subtype Specificity in Lung Cancer. Cancer Res 2021; 81:1942-1953. [PMID: 33558335 PMCID: PMC8137562 DOI: 10.1158/0008-5472.can-20-2769] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/14/2020] [Accepted: 02/03/2021] [Indexed: 11/16/2022]
Abstract
miRNA rarely possess pan-oncogenic or tumor-suppressive properties. Most miRNAs function under tissue-specific contexts, acting as either tumor suppressors in one tissue, promoting oncogenesis in another, or having no apparent role in the regulation of processes associated with the hallmarks of cancer. What has been less clear is the role of miRNAs within cell types of the same tissue and the ability within each cell type to contribute to oncogenesis. In this study, we characterize the role of one such tissue-specific miRNA, miR-31, recently identified as the most oncogenic miRNA in lung adenocarcinoma, across the histologic spectrum of human lung cancer. Compared with normal lung tissue, miR-31 was overexpressed in patient lung adenocarcinoma, squamous cell carcinoma, and large-cell neuroendocrine carcinoma, but not small-cell carcinoma or carcinoids. miR-31 promoted tumor growth in mice of xenografted human adenocarcinoma and squamous cell carcinoma cell lines, but not in large- or small-cell carcinoma lines. While miR-31 did not promote primary tumor growth of large- and small-cell carcinoma, it did promote spontaneous metastasis. Mechanistically, miR-31 altered distinct cellular signaling programs within each histologic subtype, resulting in distinct phenotypic differences. This is the first report distinguishing diverse functional roles for this miRNA across the spectrum of lung cancers and suggests that miR-31 has broad clinical value in human lung malignancy. SIGNIFICANCE: These findings demonstrate the oncogenic properties of miR-31 in specific subtypes of lung cancer and highlight it as a potential therapeutic target in these subtypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/1942/F1.large.jpg.
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MESH Headings
- Adenocarcinoma of Lung/genetics
- Adenocarcinoma of Lung/metabolism
- Adenocarcinoma of Lung/pathology
- Animals
- Carcinoma, Adenosquamous/genetics
- Carcinoma, Adenosquamous/metabolism
- Carcinoma, Adenosquamous/pathology
- Carcinoma, Large Cell/genetics
- Carcinoma, Large Cell/metabolism
- Carcinoma, Large Cell/secondary
- Carcinoma, Neuroendocrine/genetics
- Carcinoma, Neuroendocrine/metabolism
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Line, Tumor
- Cell Proliferation
- Databases, Genetic
- Female
- Humans
- Liver Neoplasms/secondary
- Lung/metabolism
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/secondary
- Male
- Mice
- Mice, Nude
- MicroRNAs/metabolism
- Neoplasm Metastasis/genetics
- Neoplasm Transplantation
- Organ Specificity
- Signal Transduction/genetics
- Small Cell Lung Carcinoma/genetics
- Small Cell Lung Carcinoma/metabolism
- Small Cell Lung Carcinoma/pathology
- Small Cell Lung Carcinoma/secondary
- Tumor Suppressor Proteins/metabolism
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Affiliation(s)
| | - John B Echols
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Austin D Silva
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joshua C Anderson
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Philip Owens
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Research Service, Department of Veterans Affairs, Denver, Colorado
| | - Clayton Yates
- Department of Biology, Tuskegee University, Tuskegee, Alabama
| | - Qing Wei
- Pathology Department, University of Alabama at Birmingham, Birmingham, Alabama
| | - Shuko Harada
- Pathology Department, University of Alabama at Birmingham, Birmingham, Alabama
| | - Douglas R Hurst
- Pathology Department, University of Alabama at Birmingham, Birmingham, Alabama
| | - Mick D Edmonds
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
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32
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Abstract
Small-cell lung cancer (SCLC) represents about 15% of all lung cancers and is marked by an exceptionally high proliferative rate, strong predilection for early metastasis and poor prognosis. SCLC is strongly associated with exposure to tobacco carcinogens. Most patients have metastatic disease at diagnosis, with only one-third having earlier-stage disease that is amenable to potentially curative multimodality therapy. Genomic profiling of SCLC reveals extensive chromosomal rearrangements and a high mutation burden, almost always including functional inactivation of the tumour suppressor genes TP53 and RB1. Analyses of both human SCLC and murine models have defined subtypes of disease based on the relative expression of dominant transcriptional regulators and have also revealed substantial intratumoural heterogeneity. Aspects of this heterogeneity have been implicated in tumour evolution, metastasis and acquired therapeutic resistance. Although clinical progress in SCLC treatment has been notoriously slow, a better understanding of the biology of disease has uncovered novel vulnerabilities that might be amenable to targeted therapeutic approaches. The recent introduction of immune checkpoint blockade into the treatment of patients with SCLC is offering new hope, with a small subset of patients deriving prolonged benefit. Strategies to direct targeted therapies to those patients who are most likely to respond and to extend the durable benefit of effective antitumour immunity to a greater fraction of patients are urgently needed and are now being actively explored.
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Affiliation(s)
- Charles M Rudin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Elisabeth Brambilla
- Institute for Advanced Biosciences, Université Grenoble Alpes, Grenoble, France
| | - Corinne Faivre-Finn
- Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Julien Sage
- Department of Pediatrics, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
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Pierret T, Toffart AC, Giaj Levra M, Moro-Sibilot D, Gobbini E. Advances and Therapeutic Perspectives in Extended-Stage Small-Cell Lung Cancer. Cancers (Basel) 2020; 12:E3224. [PMID: 33139612 PMCID: PMC7692868 DOI: 10.3390/cancers12113224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/27/2020] [Accepted: 10/30/2020] [Indexed: 01/13/2023] Open
Abstract
Extended small cell lung cancer (ED-SCLC) is a very aggressive disease, characterized by rapid growth and an early tendency to relapse. In contrast to non-small cell lung cancer, no therapeutic innovation has improved survival in patients with ED-SCLC over the past 20 years. Recently, immunotherapy has shown an important role in the management of these patients, emerging as the treatment of first choice in combination with chemotherapy and completely changing the therapeutic paradigm. However, patients' selection for this strategy is still challenging due to a lack of reliable predictive biomarkers. Conversely, the immunotherapy efficacy beyond the first line is pretty disappointing and innovative chemotherapies or target agents seem to be more promising in this setting. Some of them are also under evaluation as an upfront strategy and they will probably change the treatment algorithm in the next future. This proposal provides a comprehensive overview of available treatment strategies for ED-SCLC patients, highlighting their strengths and weaknesses.
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Affiliation(s)
- Thomas Pierret
- Thoracic Oncology Unit, CHU Grenoble-Alpes, 38700 Grenoble, France; (T.P.); (A.-C.T.); (M.G.L.); (D.M.-S.)
| | - Anne-Claire Toffart
- Thoracic Oncology Unit, CHU Grenoble-Alpes, 38700 Grenoble, France; (T.P.); (A.-C.T.); (M.G.L.); (D.M.-S.)
| | - Matteo Giaj Levra
- Thoracic Oncology Unit, CHU Grenoble-Alpes, 38700 Grenoble, France; (T.P.); (A.-C.T.); (M.G.L.); (D.M.-S.)
| | - Denis Moro-Sibilot
- Thoracic Oncology Unit, CHU Grenoble-Alpes, 38700 Grenoble, France; (T.P.); (A.-C.T.); (M.G.L.); (D.M.-S.)
| | - Elisa Gobbini
- Thoracic Oncology Unit, CHU Grenoble-Alpes, 38700 Grenoble, France; (T.P.); (A.-C.T.); (M.G.L.); (D.M.-S.)
- Cancer Research Center of Lyon, 69008 Lyon, France
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34
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Sanoyama I, Sakurai Y, Ichinoe M, Hoshino A, Kesen Y, Kato T, Numata Y, Umezawa A, Jiang SX, Murakumo Y. Increased expression of REV7 in small cell lung carcinomas and its association with tumor cell survival and proliferation. Pathol Int 2020; 71:15-23. [PMID: 33112501 DOI: 10.1111/pin.13040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/07/2020] [Indexed: 12/16/2022]
Abstract
REV7 is involved in multiple biological processes including DNA damage tolerance, cell cycle regulation and gene expression, and is an accessory subunit of the mutation-prone DNA polymerase ζ. It has been reported that REV7 expression is associated with poor prognosis in several human cancers. The aim of this study is to investigate the significance of REV7 in lung carcinogenesis. Immunohistochemical analyses of surgically resected lung cancer specimens revealed that REV7 shows an increased expression in small cell lung carcinomas (SCLCs) when compared with other histological types of lung carcinoma. Association between REV7 expression levels and clinicopathological factors was investigated using SCLC cases with or without surgical resection. Our analyses revealed that high REV7 expression significantly correlated with tumor cell proliferation, assessed by Ki-67 labeling indices, and was negatively associated with distant metastasis and extensive-stage disease. No significant association was detected between REV7 expression and other factors, including prognosis or response to chemoradiotherapy in SCLC. Increase in REV7 expression in SCLC was confirmed using SCLC cell lines. In addition, siRNA-mediated depletion of REV7 activated the apoptotic pathway and suppressed cell growth in SCLC cells. These results suggest that REV7 plays an important role in tumor cell survival and proliferation in SCLC.
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Affiliation(s)
- Itaru Sanoyama
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yasutaka Sakurai
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Masaaki Ichinoe
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Akiyoshi Hoshino
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yurika Kesen
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Takuya Kato
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yoshiko Numata
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Atsuko Umezawa
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Shi-Xu Jiang
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yoshiki Murakumo
- Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
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35
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Qiu Z, Fa P, Liu T, Prasad CB, Ma S, Hong Z, Chan ER, Wang H, Li Z, He K, Wang QE, Williams TM, Yan C, Sizemore ST, Narla G, Zhang J. A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors. Cancer Res 2020; 80:3305-3318. [PMID: 32522823 PMCID: PMC7518641 DOI: 10.1158/0008-5472.can-20-0057] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/17/2020] [Accepted: 06/04/2020] [Indexed: 01/18/2023]
Abstract
There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non-small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC in vitro and in vivo and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors. SIGNIFICANCE: This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.
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MESH Headings
- Animals
- Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors
- Biomarkers, Tumor/deficiency
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Non-Small-Cell Lung/chemistry
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Cell Line, Tumor
- Checkpoint Kinase 1/antagonists & inhibitors
- DNA Damage
- DNA Replication
- Drug Resistance, Neoplasm
- Female
- Gene Knockdown Techniques
- Genes, p53
- Genome-Wide Association Study
- Heterografts
- Humans
- Lung Neoplasms/chemistry
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Male
- Mice
- Mice, Nude
- Protein Phosphatase 2/deficiency
- Protein Phosphatase 2/genetics
- Protein Phosphatase 2/metabolism
- Proto-Oncogene Proteins c-myc/metabolism
- RNA, Small Interfering
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Affiliation(s)
- Zhaojun Qiu
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Pengyan Fa
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Tao Liu
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Chandra B Prasad
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Shanhuai Ma
- University of Rochester, Rochester, New York
| | - Zhipeng Hong
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Ernest R Chan
- Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland
| | - Zaibo Li
- Department of Pathology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Kai He
- Department of Internal Medicine, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Qi-En Wang
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Terence M Williams
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Chunhong Yan
- Georgia Cancer Center, Augusta University, Augusta, Georgia
| | - Steven T Sizemore
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio
| | - Goutham Narla
- Department of Medicine, University of Michigan, Ann Arbor, Michigan
| | - Junran Zhang
- Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio.
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36
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Coles GL, Cristea S, Webber JT, Levin RS, Moss SM, He A, Sangodkar J, Hwang YC, Arand J, Drainas AP, Mooney NA, Demeter J, Spradlin JN, Mauch B, Le V, Shue YT, Ko JH, Lee MC, Kong C, Nomura DK, Ohlmeyer M, Swaney DL, Krogan NJ, Jackson PK, Narla G, Gordan JD, Shokat KM, Sage J. Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells. Cancer Cell 2020; 38:129-143.e7. [PMID: 32531271 PMCID: PMC7363571 DOI: 10.1016/j.ccell.2020.05.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 02/18/2020] [Accepted: 05/04/2020] [Indexed: 12/23/2022]
Abstract
Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.
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Affiliation(s)
- Garry L Coles
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Sandra Cristea
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - James T Webber
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA
| | - Rebecca S Levin
- Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Steven M Moss
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Andy He
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Jaya Sangodkar
- Division of Genetic Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Yeonjoo C Hwang
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Julia Arand
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Alexandros P Drainas
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Nancie A Mooney
- Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA
| | - Janos Demeter
- Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA
| | - Jessica N Spradlin
- Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Brandon Mauch
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Vicky Le
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Yan Ting Shue
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Julie H Ko
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Myung Chang Lee
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Christina Kong
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Daniel K Nomura
- Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Michael Ohlmeyer
- Icahn School of Medicine at Mount Sinai, New York, NY, USA; Atux Iskay LLC, Plainsboro, New Jersey, NJ 08536, USA
| | - Danielle L Swaney
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; David J. Gladstone Institute, University of California San Francisco, San Francisco, CA 94158, USA
| | - Nevan J Krogan
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; David J. Gladstone Institute, University of California San Francisco, San Francisco, CA 94158, USA
| | - Peter K Jackson
- Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Goutham Narla
- Division of Genetic Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - John D Gordan
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA
| | - Kevan M Shokat
- Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Julien Sage
- Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
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37
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Zhao D, Xie B, Yang Y, Yan P, Liang SN, Lin Q. Progress in immunotherapy for small cell lung cancer. World J Clin Oncol 2020; 11:370-377. [PMID: 32874950 PMCID: PMC7450814 DOI: 10.5306/wjco.v11.i6.370] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/18/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
Small-cell lung cancer (SCLC) is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors. At present, radiotherapy and chemotherapy remain the mainstay of treatment for SCLC. Progress in targeted therapies for SCLC with driver mutations has been slow, and these therapies are still under investigation in preclinical or early-phase clinical trials, and research on antiangiogenic tyrosine kinase inhibitors (e.g., anlotinib) has achieved some success. Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy. In this article we review the recent advances in immunotherapy for SCLC.
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Affiliation(s)
- Dong Zhao
- Department of Oncology, The People’s Hospital of Lixin County, Bozhou 236700, Anhui Province, China
| | - Bing Xie
- Department of Oncology, The People’s Hospital of Lixin County, Bozhou 236700, Anhui Province, China
| | - Yong Yang
- Department of Oncology, The People’s Hospital of Lixin County, Bozhou 236700, Anhui Province, China
| | - Peng Yan
- Department of Oncology, The People’s Hospital of Lixin County, Bozhou 236700, Anhui Province, China
| | - Sheng-Nan Liang
- Department of Oncology, The People’s Hospital of Lixin County, Bozhou 236700, Anhui Province, China
| | - Qiang Lin
- Department of Oncology, North China Petroleum Bureau General Hospital, Hebei Medical University, Renqiu 062552, Hebei Province, China
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38
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Nyquist MD, Corella A, Coleman I, De Sarkar N, Kaipainen A, Ha G, Gulati R, Ang L, Chatterjee P, Lucas J, Pritchard C, Risbridger G, Isaacs J, Montgomery B, Morrissey C, Corey E, Nelson PS. Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress. Cell Rep 2020; 31:107669. [PMID: 32460015 PMCID: PMC7453577 DOI: 10.1016/j.celrep.2020.107669] [Citation(s) in RCA: 179] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 03/22/2020] [Accepted: 04/29/2020] [Indexed: 12/24/2022] Open
Abstract
Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determine the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1-deficient tumors are classified as AR-active adenocarcinomas, indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss is associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 are highly resistant to all single-agent therapeutics tested, the combination of PARP and ATR inhibition is found to produce significant responses, reflecting a clinically exploitable vulnerability resulting from replication stress.
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Affiliation(s)
- Michael D Nyquist
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Alexandra Corella
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Ilsa Coleman
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Navonil De Sarkar
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Arja Kaipainen
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Gavin Ha
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Roman Gulati
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Lisa Ang
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Payel Chatterjee
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Jared Lucas
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Colin Pritchard
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
| | - Gail Risbridger
- Department of Anatomy and Cell Biology, Monash University, Melbourne, VIC 3000, Australia
| | - John Isaacs
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA
| | - Bruce Montgomery
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Colm Morrissey
- Department of Urology, University of Washington, Seattle, WA 98195, USA
| | - Eva Corey
- Department of Urology, University of Washington, Seattle, WA 98195, USA
| | - Peter S Nelson
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Urology, University of Washington, Seattle, WA 98195, USA.
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39
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Taniguchi H, Sen T, Rudin CM. Targeted Therapies and Biomarkers in Small Cell Lung Cancer. Front Oncol 2020; 10:741. [PMID: 32509576 PMCID: PMC7251180 DOI: 10.3389/fonc.2020.00741] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid growth, early metastasis, and acquired therapeutic resistance. A majority of patients with SCLC have extensive-stage (ES) disease, defined as the presence of metastatic disease outside the hemithorax at first diagnosis. SCLC has been considered “a graveyard for drug development,” with chemotherapy remaining the standard treatment for first- and second-line management until quite recently. In contrast to NSCLC, identifying therapeutic targets in SCLC has been challenging, partly because driver mutations are primarily loss of function, involving the tumor suppressor genes RB1 and TP53 or currently untargetable (e.g., amplification of MYC family members). Recent gene expression profiling of SCLC cells lines, patient samples and representative murine models, have led to a proposed delineation of four major subtypes for SCLC distinguished by differential expression of four key transcriptional regulators (ASCL1, NEUROD1, POU2F3, and YAP1). Our understanding of the biology of SCLC has indeed significantly improved recently due to the continued efforts of the dedicated investigators in this field, but the therapeutic options remain dismal. While recent results from immunotherapy trials are encouraging, most patients demonstrate either primary or rapid acquired resistance to current regimens, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. In this opinion article, we will discuss recent developments in the treatment of SCLC, focused on current understanding of the signaling pathways, the role of immunotherapy and targeted therapy, and emerging biomarkers of response to therapy in SCLC.
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Affiliation(s)
- Hirokazu Taniguchi
- Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Triparna Sen
- Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Charles M Rudin
- Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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40
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Liao Y, Wang Y, Cheng M, Huang C, Fan X. Weighted Gene Coexpression Network Analysis of Features That Control Cancer Stem Cells Reveals Prognostic Biomarkers in Lung Adenocarcinoma. Front Genet 2020; 11:311. [PMID: 32391047 PMCID: PMC7192063 DOI: 10.3389/fgene.2020.00311] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 03/16/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose We aimed to identify new prognostic biomarkers of lung adenocarcinoma (LUAD) based on cancer stem cell theory. Materials and Methods: RNA-seq and microarray data were obtained with clinical information downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Weighted gene coexpression network analysis (WGCNA) was applied to identify significant module and hub genes. The hub genes were validated via microarray data from GEO, and a prognostic signature with prognostic hub genes was constructed. Results LUAD patients enrolled from TCGA had a higher mRNA expression-based stemness index (mRNAsi) in tumor tissue than in adjacent normal tissue. Some clinical features and prognoses were found to be highly correlated with mRNAsi. WGCNA found that the green module and blue module were the most significant modules related to mRNAsi; 50 key genes were identified in the green module and were enriched mostly in the cell cycle, chromosome segregation, chromosomal region and microtubule binding. Six hub genes were revealed through the protein-protein interaction (PPI) network and Molecular Complex Detection (MCODE) plugin of Cytoscape software. Based on external verification with the GEO database, these six genes are not only expressed at different levels in LUAD and normal tissues but also associated with different clinical features. In addition, the construction of a prognostic signature with three hub genes showed high predictive value. Conclusion mRNAsi-related biomarkers may suggest a new potential treatment strategy for LUAD.
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Affiliation(s)
- Yi Liao
- Department of Respiratory and Critical Care Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yulei Wang
- Department of Respiratory and Critical Care Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Mengqing Cheng
- Department of Respiratory and Critical Care Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chengliang Huang
- Department of Respiratory and Critical Care Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xianming Fan
- Department of Respiratory and Critical Care Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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41
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Poirier JT, George J, Owonikoko TK, Berns A, Brambilla E, Byers LA, Carbone D, Chen HJ, Christensen CL, Dive C, Farago AF, Govindan R, Hann C, Hellmann MD, Horn L, Johnson JE, Ju YS, Kang S, Krasnow M, Lee J, Lee SH, Lehman J, Lok B, Lovly C, MacPherson D, McFadden D, Minna J, Oser M, Park K, Park KS, Pommier Y, Quaranta V, Ready N, Sage J, Scagliotti G, Sos ML, Sutherland KD, Travis WD, Vakoc CR, Wait SJ, Wistuba I, Wong KK, Zhang H, Daigneault J, Wiens J, Rudin CM, Oliver TG. New Approaches to SCLC Therapy: From the Laboratory to the Clinic. J Thorac Oncol 2020; 15:520-540. [PMID: 32018053 PMCID: PMC7263769 DOI: 10.1016/j.jtho.2020.01.016] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/10/2020] [Accepted: 01/11/2020] [Indexed: 12/12/2022]
Abstract
The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.
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Affiliation(s)
- John T Poirier
- Perlmutter Cancer Center, New York University Langone Health, New York, New York
| | - Julie George
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne Germany
| | | | - Anton Berns
- The Netherlands Cancer Institute, Amsterdam, Netherlands
| | | | | | | | | | | | - Caroline Dive
- Cancer Research United Kingdom, Manchester Institute, Manchester, United Kingdom
| | - Anna F Farago
- Massachusetts General Hospital, Boston, Massachusetts
| | | | - Christine Hann
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Leora Horn
- Vanderbilt University, Nashville, Tennessee
| | | | | | - Sumin Kang
- Emory University, Winship Cancer Institute, Atlanta, Georgia
| | - Mark Krasnow
- Stanford University School of Medicine, Stanford, California
| | - James Lee
- The Ohio State University, Columbus, Ohio
| | - Se-Hoon Lee
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | | | - Benjamin Lok
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | | | | | | | - John Minna
- UT Southwestern Medical Center, Dallas, Texas
| | - Matthew Oser
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | | | - Yves Pommier
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | | | - Julien Sage
- Stanford University School of Medicine, Stanford, California
| | | | - Martin L Sos
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne Germany; Molecular Pathology, Institute of Pathology, University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Kate D Sutherland
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | | | | | - Sarah J Wait
- Huntsman Cancer Institute and University of Utah, Salt Lake City, Utah
| | | | - Kwok Kin Wong
- Perlmutter Cancer Center, New York University Langone Health, New York, New York
| | - Hua Zhang
- Perlmutter Cancer Center, New York University Langone Health, New York, New York
| | - Jillian Daigneault
- International Association for the Study of Lung Cancer, Aurora, Colorado
| | - Jacinta Wiens
- International Association for the Study of Lung Cancer, Aurora, Colorado
| | | | - Trudy G Oliver
- Huntsman Cancer Institute and University of Utah, Salt Lake City, Utah.
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42
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Lum C, Alamgeer M. Technological and Therapeutic Advances in Advanced Small Cell Lung Cancer. Cancers (Basel) 2019; 11:E1570. [PMID: 31619019 PMCID: PMC6826371 DOI: 10.3390/cancers11101570] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 12/17/2022] Open
Abstract
Small cell lung cancer (SCLC) accounts for approximately 10-15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival in the last 30 years. Historically, experiments performed on conventional cell lines may have limitations of not accurately reflecting the complex biological and genomic heterogeneity of this disease. However, additional knowledge gained from recently developed genetically engineered mouse models (GEMMs) and patient derived xenografts (PDXs) have made encouraging inroads. Whole genome sequencing (WGS) data reveals a high mutational burden and a number of genetic alterations but low frequency of targetable mutations. Despite several failures, considerable therapeutic opportunities have recently emerged. Potentially promising therapies include those targeting DNA damage repair, stem cell/renewal and drug resistant mechanisms. Modest success has also been achieved with immune checkpoint inhibitors while therapeutic exploration of various other components of the immune system is underway. However, the complex heterogeneities reflect the need for accurate bio-markers to translate novel discoveries into clinical benefit. Additionally, the molecular mechanisms that differentiate chemo-sensitive from chemo-refractory disease remain unknown. Obtaining reliable tumour samples by utilising novel techniques such as endobronchial ultrasound guided needle aspiration or adopting to liquid biopsies are becoming popular. This review will focus on recent technological and therapeutic advancements to surmount this recalcitrant disease.
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Affiliation(s)
- Caroline Lum
- Department of Medical Oncology, Monash Health and Monash University, Clayton, VIC 3168, Australia.
| | - Muhammad Alamgeer
- Department of Medical Oncology, Monash Health and Monash University, Clayton, VIC 3168, Australia.
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia.
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43
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Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment. Cancers (Basel) 2019; 11:cancers11091289. [PMID: 31480716 PMCID: PMC6770306 DOI: 10.3390/cancers11091289] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 08/22/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.
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44
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Mak DW, Li S, Minchom A. Challenging the recalcitrant disease—developing molecularly driven treatments for small cell lung cancer. Eur J Cancer 2019; 119:132-150. [DOI: 10.1016/j.ejca.2019.04.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/11/2019] [Accepted: 04/26/2019] [Indexed: 12/29/2022]
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Erber J, Steiner JD, Isensee J, Lobbes LA, Toschka A, Beleggia F, Schmitt A, Kaiser RWJ, Siedek F, Persigehl T, Hucho T, Reinhardt HC. Dual Inhibition of GLUT1 and the ATR/CHK1 Kinase Axis Displays Synergistic Cytotoxicity in KRAS-Mutant Cancer Cells. Cancer Res 2019; 79:4855-4868. [PMID: 31405847 DOI: 10.1158/0008-5472.can-18-3959] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 06/18/2019] [Accepted: 08/06/2019] [Indexed: 11/16/2022]
Abstract
The advent of molecularly targeted therapeutic agents has opened a new era in cancer therapy. However, many tumors rely on nondruggable cancer-driving lesions. In addition, long-lasting clinical benefits from single-agent therapies rarely occur, as most of the tumors acquire resistance over time. The identification of targeted combination regimens interfering with signaling through oncogenically rewired pathways provides a promising approach to enhance efficacy of single-agent-targeted treatments. Moreover, combination drug therapies might overcome the emergence of drug resistance. Here, we performed a focused flow cytometry-based drug synergy screen and identified a novel synergistic interaction between GLUT1-mediated glucose transport and the cell-cycle checkpoint kinases ATR and CHK1. Combined inhibition of CHK1/GLUT1 or ATR/GLUT1 robustly induced apoptosis, particularly in RAS-mutant cancer cells. Mechanistically, combined inhibition of ATR/CHK1 and GLUT1 arrested sensitive cells in S-phase and led to the accumulation of genotoxic damage, particularly in S-phase. In vivo, simultaneous inhibition of ATR and GLUT1 significantly reduced tumor volume gain in an autochthonous mouse model of KrasG12D -driven soft tissue sarcoma. Taken together, these findings pave the way for combined inhibition of GLUT1 and ATR/CHK1 as a therapeutic approach for KRAS-driven cancers. SIGNIFICANCE: Dual targeting of the DNA damage response and glucose transport synergistically induces apoptosis in KRAS-mutant cancer, suggesting this combination treatment for clinical validation in KRAS-stratified tumor patients.
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Affiliation(s)
- Johanna Erber
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
| | - Joachim D Steiner
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jörg Isensee
- Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Leonard A Lobbes
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - André Toschka
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Filippo Beleggia
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Anna Schmitt
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Rainer W J Kaiser
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Florian Siedek
- Institute of Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thorsten Persigehl
- Institute of Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Tim Hucho
- Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hans C Reinhardt
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
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46
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Balanis NG, Sheu KM, Esedebe FN, Patel SJ, Smith BA, Park JW, Alhani S, Gomperts BN, Huang J, Witte ON, Graeber TG. Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies. Cancer Cell 2019; 36:17-34.e7. [PMID: 31287989 PMCID: PMC6703903 DOI: 10.1016/j.ccell.2019.06.005] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 03/04/2019] [Accepted: 06/06/2019] [Indexed: 01/01/2023]
Abstract
Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies.
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Affiliation(s)
- Nikolas G Balanis
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
| | - Katherine M Sheu
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
| | - Favour N Esedebe
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
| | - Saahil J Patel
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
| | - Bryan A Smith
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA
| | - Jung Wook Park
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA
| | - Salwan Alhani
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
| | - Brigitte N Gomperts
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA
| | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Durham, NC 27708, USA
| | - Owen N Witte
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.
| | - Thomas G Graeber
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.
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47
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Böttger F, Semenova EA, Song JY, Ferone G, van der Vliet J, Cozijnsen M, Bhaskaran R, Bombardelli L, Piersma SR, Pham TV, Jimenez CR, Berns A. Tumor Heterogeneity Underlies Differential Cisplatin Sensitivity in Mouse Models of Small-Cell Lung Cancer. Cell Rep 2019; 27:3345-3358.e4. [PMID: 31189116 PMCID: PMC6581744 DOI: 10.1016/j.celrep.2019.05.057] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/26/2019] [Accepted: 05/15/2019] [Indexed: 12/17/2022] Open
Abstract
Small-cell lung cancer is the most aggressive type of lung cancer, characterized by a remarkable response to chemotherapy followed by development of resistance. Here, we describe SCLC subtypes in Mycl- and Nfib-driven GEMM that include CDH1-high peripheral primary tumor lesions and CDH1-negative, aggressive intrapulmonary metastases. Cisplatin treatment preferentially eliminates the latter, thus revealing a striking differential response. Using a combined transcriptomic and proteomic approach, we find a marked reduction in proliferation and metabolic rewiring following cisplatin treatment and present evidence for a distinctive metabolic and structural profile defining intrinsically resistant populations. This offers perspectives for effective combination therapies that might also hold promise for treating human SCLC, given the very similar response of both mouse and human SCLC to cisplatin.
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Affiliation(s)
- Franziska Böttger
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, 1081 HV Amsterdam, the Netherlands
| | - Ekaterina A Semenova
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Ji-Ying Song
- Department of Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Giustina Ferone
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Jan van der Vliet
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Miranda Cozijnsen
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Rajith Bhaskaran
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Lorenzo Bombardelli
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Sander R Piersma
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, 1081 HV Amsterdam, the Netherlands
| | - Thang V Pham
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, 1081 HV Amsterdam, the Netherlands
| | - Connie R Jimenez
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, 1081 HV Amsterdam, the Netherlands.
| | - Anton Berns
- Oncode Institute, Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
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48
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Zimmerman S, Das A, Wang S, Julian R, Gandhi L, Wolf J. 2017-2018 Scientific Advances in Thoracic Oncology: Small Cell Lung Cancer. J Thorac Oncol 2019; 14:768-783. [PMID: 30763729 DOI: 10.1016/j.jtho.2019.01.022] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 01/22/2019] [Accepted: 01/22/2019] [Indexed: 01/04/2023]
Abstract
SCLC remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic profiling, multiple new targets are showing promise in the clinical arena, and just recently programmed death ligand 1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended-disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immunotherapy and targeted therapies based on specific biomarkers and rational combinations. Here we discuss the preclinical and clinical strides in 2017 and 2018 that put us on the threshold of a new era in therapeutics and will, it is hoped, translate into significant improvements in survival.
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Affiliation(s)
- Stefan Zimmerman
- Oncology Department, Service of Immuno-Oncology, Lausanne University Hospital, Lausanne, Switzerland.
| | - Arundhati Das
- New York University Langone Health, New York, New York
| | - Shuhang Wang
- Peking University Cancer Hospital, Beijing, People's Republic of China
| | - Ricklie Julian
- New York University Langone Health, New York, New York; Laura and Isaac Perlmutter Cancer Center, New York, New York; New York University School of Medicine, New York, New York
| | - Leena Gandhi
- New York University Langone Health, New York, New York; Laura and Isaac Perlmutter Cancer Center, New York, New York; New York University School of Medicine, New York, New York
| | - Juergen Wolf
- Center for Integrated Oncology Köln Bonn, University Clinic Köln, Köln, Germany
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Nagel R, Avelar AT, Aben N, Proost N, van de Ven M, van der Vliet J, Cozijnsen M, de Vries H, Wessels LFA, Berns A. Inhibition of the Replication Stress Response Is a Synthetic Vulnerability in SCLC That Acts Synergistically in Combination with Cisplatin. Mol Cancer Ther 2019; 18:762-770. [PMID: 30872379 DOI: 10.1158/1535-7163.mct-18-0972] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/20/2018] [Accepted: 02/22/2019] [Indexed: 12/20/2022]
Abstract
Small cell lung cancer (SCLC) is generally regarded as very difficult to treat, mostly due to the development of metastases early in the disease and a quick relapse with resistant disease. SCLC patients initially show a good response to treatment with the DNA damaging agents cisplatin and etoposide. This is, however, quickly followed by the development of resistant disease, which urges the development of novel therapies for this type of cancer. In this study, we set out to compile a comprehensive overview of the vulnerabilities of SCLC. A functional genome-wide screen where all individual genes were knocked out was performed to identify novel vulnerabilities of SCLC. By analysis of the knockouts that were lethal to these cancer cells, we identified several processes to be synthetic vulnerabilities in SCLC. We were able to validate the vulnerability to inhibition of the replication stress response machinery by use of Chk1 and ATR inhibitors. Strikingly, SCLC cells were more sensitive to these inhibitors than nontransformed cells. In addition, these inhibitors work synergistically with either etoposide and cisplatin, where the interaction is largest with the latter. ATR inhibition by VE-822 treatment in combination with cisplatin also outperforms the combination of cisplatin with etoposide in vivo Altogether, our study uncovered a critical dependence of SCLC on the replication stress response and urges the validation of ATR inhibitors in combination with cisplatin in a clinical setting.
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Affiliation(s)
- Remco Nagel
- Oncode Institute, Amsterdam, the Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Ana Teresa Avelar
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Nanne Aben
- Oncode Institute, Amsterdam, the Netherlands
- Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Natalie Proost
- Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Marieke van de Ven
- Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jan van der Vliet
- Oncode Institute, Amsterdam, the Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Miranda Cozijnsen
- Oncode Institute, Amsterdam, the Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Hilda de Vries
- Oncode Institute, Amsterdam, the Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Lodewyk F A Wessels
- Oncode Institute, Amsterdam, the Netherlands
- Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Anton Berns
- Oncode Institute, Amsterdam, the Netherlands.
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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50
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Mani C, Pai S, Papke CM, Palle K, Gmeiner WH. Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition. Neoplasia 2018; 20:1236-1245. [PMID: 30439567 PMCID: PMC6232621 DOI: 10.1016/j.neo.2018.10.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 10/15/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
We are developing the fluoropyrimidine polymer F10 to overcome limitations of 5-fluorouracil (5-FU) that result from inefficient metabolism to 5-fluoro-2′-deoxyuridine-5′-mono- and tri-phosphate, the deoxyribonucleotide metabolites that are responsible for 5-FU's anticancer activity. F10 is much more cytotoxic than 5-FU to colorectal cancer (CRC) cells; however, the mechanism of enhanced F10 cytotoxicity remains incompletely characterized. Using DNA fiber analysis, we establish that F10 decreases replication fork velocity and causes replication fork collapse, while 1000-fold excess of 5-FU is required to achieve similar endpoints. Treatment of HCT-116 cells with F10 results in Chk1 phosphorylation and activation of intra–S-phase checkpoint. Combining F10 with pharmacological inhibition of Chk1 with either PF-477736 or prexasertib in CRC cells enhanced DNA damage relative to single-agent treatment as assessed by γH2AX intensity and COMET assay. PF-477736 or prexasertib co-treatment also inhibited upregulation of Rad51 levels in response to F10, resulting in reduced homologous repair. siRNA knockdown of Chk1 also increased F10-induced DNA damage assessed and sensitized CRC cells to F10. However, Chk1 knockdown did not inhibit Rad51 upregulation by F10, indicating that the scaffolding activity of Chk1 imparts activity in DNA repair distinct from Chk1 enzymatic activity. Our results indicate that F10 is cytotoxic to CRC cells in part through DNA damage subsequent to replication fork collapse. F10 is ~1000-fold more potent than 5-FU at inducing replication-mediated DNA damage which correlates with the increased overall potency of F10 relative to 5-FU. F10 efficacy can be enhanced by pharmacological inhibition of Chk1.
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Affiliation(s)
- Chinnadurai Mani
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604
| | - Sachin Pai
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604
| | - Cinta Maria Papke
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604
| | - Komaraiah Palle
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604.
| | - William H Gmeiner
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157.
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