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

Nuclear Dynamics and Cancer (NDC)

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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
Pages (from-to)	eadg2263
Journal	Science advances
Volume	9
Issue number	47
DOIs	https://doi.org/10.1126/sciadv.adg2263
State	Published - Nov 24 2023

Keywords

Antineoplastic Agents/pharmacology
Ataxia Telangiectasia
Ataxia Telangiectasia Mutated Proteins/genetics
DNA Damage
DNA Repair
Humans
Poly(ADP-ribose) Polymerases/genetics
Tumor Microenvironment
Urinary Bladder Neoplasms/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/sciadv.adg2263

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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), eadg2263. Article eadg2263. https://doi.org/10.1126/sciadv.adg2263

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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.",

keywords = "Antineoplastic Agents/pharmacology, Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins/genetics, DNA Damage, DNA Repair, Humans, Poly(ADP-ribose) Polymerases/genetics, Tumor Microenvironment, Urinary Bladder Neoplasms/genetics",

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 Wu, {Chin Lee} and Efstathiou, {Jason A.} and Miyamoto, {David T.} and William Anderson and Zoltan Szallasi and Mouw, {Kent W.}",

note = "2375-2548 Zhou, Yuzhen Orcid: 0000-0003-0461-2963 B{\"o}rcs{\"o}k, Judit Orcid: 0000-0002-3290-3971 Adib, Elio Orcid: 0000-0003-0594-7976 Kamran, Sophia C Orcid: 0000-0001-9283-6515 Neil, Alexander J Stawiski, Konrad Orcid: 0000-0002-6550-3384 Freeman, Dory Stormoen, Dag Rune Orcid: 0000-0003-2928-9218 Sztupinszki, Zsofia Orcid: 0000-0002-8691-4086 Samant, Amruta Nassar, Amin Orcid: 0000-0002-8084-9105 Bekele, Raie T Hanlon, Timothy Valentine, Henkel Epstein, Ilana Sharma, Bijaya Felt, Kristen Abbosh, Philip Wu, Chin-Lee Orcid: 0000-0002-0444-0068 Efstathiou, Jason A Orcid: 0000-0003-0996-0350 Miyamoto, David T Orcid: 0000-0003-3692-8823 Anderson, William Szallasi, Zoltan Orcid: 0000-0001-5395-7509 Mouw, Kent W Orcid: 0000-0001-7939-7343 U01 CA260369/CA/NCI NIH HHS/United States C06 CA059267/CA/NCI NIH HHS/United States P01 CA228696/CA/NCI NIH HHS/United States R01 CA272657/CA/NCI NIH HHS/United States R01 CA259007/CA/NCI NIH HHS/United States P30 CA006516/CA/NCI NIH HHS/United States Journal Article United States 2023/11/22 Sci Adv. 2023 Nov 24;9(47):eadg2263. doi: 10.1126/sciadv.adg2263. Epub 2023 Nov 22. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved;",

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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, CL, 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, pp. eadg2263. https://doi.org/10.1126/sciadv.adg2263

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 - 2375-2548 Zhou, Yuzhen Orcid: 0000-0003-0461-2963 Börcsök, Judit Orcid: 0000-0002-3290-3971 Adib, Elio Orcid: 0000-0003-0594-7976 Kamran, Sophia C Orcid: 0000-0001-9283-6515 Neil, Alexander J Stawiski, Konrad Orcid: 0000-0002-6550-3384 Freeman, Dory Stormoen, Dag Rune Orcid: 0000-0003-2928-9218 Sztupinszki, Zsofia Orcid: 0000-0002-8691-4086 Samant, Amruta Nassar, Amin Orcid: 0000-0002-8084-9105 Bekele, Raie T Hanlon, Timothy Valentine, Henkel Epstein, Ilana Sharma, Bijaya Felt, Kristen Abbosh, Philip Wu, Chin-Lee Orcid: 0000-0002-0444-0068 Efstathiou, Jason A Orcid: 0000-0003-0996-0350 Miyamoto, David T Orcid: 0000-0003-3692-8823 Anderson, William Szallasi, Zoltan Orcid: 0000-0001-5395-7509 Mouw, Kent W Orcid: 0000-0001-7939-7343 U01 CA260369/CA/NCI NIH HHS/United States C06 CA059267/CA/NCI NIH HHS/United States P01 CA228696/CA/NCI NIH HHS/United States R01 CA272657/CA/NCI NIH HHS/United States R01 CA259007/CA/NCI NIH HHS/United States P30 CA006516/CA/NCI NIH HHS/United States Journal Article United States 2023/11/22 Sci Adv. 2023 Nov 24;9(47):eadg2263. doi: 10.1126/sciadv.adg2263. Epub 2023 Nov 22. Publisher Copyright: Copyright © 2023 The Authors, some rights reserved;

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.

KW - Antineoplastic Agents/pharmacology

KW - Ataxia Telangiectasia

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - DNA Damage

KW - DNA Repair

KW - Humans

KW - Poly(ADP-ribose) Polymerases/genetics

KW - Tumor Microenvironment

KW - Urinary Bladder Neoplasms/genetics

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

U2 - 10.1126/sciadv.adg2263

DO - 10.1126/sciadv.adg2263

M3 - Article

C2 - 37992168

SN - 2375-2548

VL - 9

SP - eadg2263

JO - Science advances

JF - Science advances

IS - 47

M1 - eadg2263

ER -

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer

Abstract

Keywords

UN SDGs

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