ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer

Yuzhen Zhou; Judit Börcsök; Elio Adib; Sophia C Kamran; Alexander J Neil; Konrad Stawiski; Dory Freeman; Dag Rune Stormoen; Zsofia Sztupinszki; Amruta Samant; Amin Nassar; Raie T Bekele; Timothy Hanlon; Henkel Valentine; Ilana Epstein; Bijaya Sharma; Kristen Felt; Philip Abbosh; Chin-Lee Wu; Jason A Efstathiou; David T Miyamoto; William Anderson; Zoltan Szallasi; Kent W Mouw

doi:10.1126/sciadv.adg2263

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer

Yuzhen Zhou, Judit Börcsök, Elio Adib, Sophia C Kamran, Alexander J Neil, Konrad Stawiski, Dory Freeman, Dag Rune Stormoen, Zsofia Sztupinszki, Amruta Samant, Amin Nassar, Raie T Bekele, Timothy Hanlon, Henkel Valentine, Ilana Epstein, Bijaya Sharma, Kristen Felt, Philip Abbosh, Chin-Lee Wu, Jason A EfstathiouDavid T Miyamoto, William Anderson, Zoltan Szallasi, Kent W Mouw^*

^*Corresponding author for this work

Department of Oncology

Abstract

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.

Original language	English
Article number	eadg2263
Journal	Science Advances
Volume	9
Issue number	47
Number of pages	15
DOIs	https://doi.org/10.1126/sciadv.adg2263
Publication status	Published - 24 Nov 2023

Access to Document

10.1126/sciadv.adg2263

Cite this

Zhou, Y., Börcsök, J., Adib, E., Kamran, S. C., Neil, A. J., Stawiski, K., Freeman, D., Stormoen, D. R., Sztupinszki, Z., Samant, A., Nassar, A., Bekele, R. T., Hanlon, T., Valentine, H., Epstein, I., Sharma, B., Felt, K., Abbosh, P., Wu, C.-L., ... Mouw, K. W. (2023). ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer. Science Advances, 9(47), Article eadg2263. https://doi.org/10.1126/sciadv.adg2263

Zhou, Y, Börcsök, J, Adib, E, Kamran, SC, Neil, AJ, Stawiski, K, Freeman, D, Stormoen, DR, Sztupinszki, Z, Samant, A, Nassar, A, Bekele, RT, Hanlon, T, Valentine, H, Epstein, I, Sharma, B, Felt, K, Abbosh, P, Wu, C-L, Efstathiou, JA, Miyamoto, DT, Anderson, W, Szallasi, Z & Mouw, KW 2023, 'ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer', Science Advances, vol. 9, no. 47, eadg2263. https://doi.org/10.1126/sciadv.adg2263

@article{91e03a9d3b84444c89f8e599b6f8cf0e,

title = "ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer",

abstract = "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.",

author = "Yuzhen Zhou and Judit B{\"o}rcs{\"o}k and Elio Adib and Kamran, {Sophia C} and Neil, {Alexander J} and Konrad Stawiski and Dory Freeman and Stormoen, {Dag Rune} and Zsofia Sztupinszki and Amruta Samant and Amin Nassar and Bekele, {Raie T} and Timothy Hanlon and Henkel Valentine and Ilana Epstein and Bijaya Sharma and Kristen Felt and Philip Abbosh and Chin-Lee Wu and Efstathiou, {Jason A} and Miyamoto, {David T} and William Anderson and Zoltan Szallasi and Mouw, {Kent W}",

year = "2023",

month = nov,

day = "24",

doi = "10.1126/sciadv.adg2263",

language = "English",

volume = "9",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "47",

}

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

PY - 2023/11/24

Y1 - 2023/11/24

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.

UR - http://www.scopus.com/inward/record.url?scp=85177976566&partnerID=8YFLogxK

U2 - 10.1126/sciadv.adg2263

DO - 10.1126/sciadv.adg2263

M3 - Journal article

C2 - 37992168

SN - 2375-2548

VL - 9

JO - Science Advances

JF - Science Advances

IS - 47

M1 - eadg2263

ER -

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer

Abstract

Access to Document

Other files and links

Fingerprint

Cite this