ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer
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ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer. / Zhou, Yuzhen; Börcsök, Judit; Adib, Elio; Kamran, Sophia C.; Neil, Alexander J.; Stawiski, Konrad; Freeman, Dory; Stormoen, Dag Rune; Sztupinszki, Zsofia; Samant, Amruta; Nassar, Amin; Bekele, Raie T.; Hanlon, Timothy; Valentine, Henkel; Epstein, Ilana; Sharma, Bijaya; Felt, Kristen; Abbosh, Philip; Wu, Chin Lee; Efstathiou, Jason A.; Miyamoto, David T.; Anderson, William; Szallasi, Zoltan; Mouw, Kent W.
In: Science Advances, Vol. 9, No. 47, eadg2263, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer
AU - Zhou, Yuzhen
AU - Börcsök, Judit
AU - Adib, Elio
AU - Kamran, Sophia C.
AU - Neil, Alexander J.
AU - Stawiski, Konrad
AU - Freeman, Dory
AU - Stormoen, Dag Rune
AU - Sztupinszki, Zsofia
AU - Samant, Amruta
AU - Nassar, Amin
AU - Bekele, Raie T.
AU - Hanlon, Timothy
AU - Valentine, Henkel
AU - Epstein, Ilana
AU - Sharma, Bijaya
AU - Felt, Kristen
AU - Abbosh, Philip
AU - Wu, Chin Lee
AU - Efstathiou, Jason A.
AU - Miyamoto, David T.
AU - Anderson, William
AU - Szallasi, Zoltan
AU - Mouw, Kent W.
N1 - Publisher Copyright: Copyright © 2023 The Authors, some rights reserved;
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1126/sciadv.adg2263
DO - 10.1126/sciadv.adg2263
M3 - Journal article
C2 - 37992168
AN - SCOPUS:85177976566
VL - 9
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 47
M1 - eadg2263
ER -
ID: 378951015