ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer
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Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair–targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer.
Originalsprog | Engelsk |
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Artikelnummer | eadg2263 |
Tidsskrift | Science Advances |
Vol/bind | 9 |
Udgave nummer | 47 |
Antal sider | 16 |
ISSN | 2375-2548 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Support Grant # NIH 5 P30 CA06516. Funding: This work was supported by NCI (R01CA272657 to K.W.M., R01CA259007 to D.T.M., C06CA059267 to J.A.E., and U01CA260369 to P.A.), the Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 and 2017-1.2.1-NKP-2017-00002 to Z.Sza.), the Breast Cancer Research Foundation (BCRF-21-159 to Z.S.), Kræftens Bekæmpelse (R281-A16566 to Z.S.), the Department of Defense through the Prostate Cancer Research Program (W81XWH-18-2-0056 to Z.S.), Det Frie Forskningsråd Sundhed og Sygdom (7016-00345B to Z.S.), NIH (P01CA228696-01A1 to Z.S.), and the Radiation Oncology Institute (to D.T.M.)
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Copyright © 2023 The Authors, some rights reserved;
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