ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer-Reference-Cited by-同舟云学术

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer

Published:2023-11-24 Issue:47 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Zhou Yuzhen¹^ORCID,Börcsök Judit²³^ORCID,Adib Elio⁴^ORCID,Kamran Sophia C.⁵⁶⁷^ORCID,Neil Alexander J.⁸,Stawiski Konrad¹⁹^ORCID,Freeman Dory¹⁰,Stormoen Dag Rune¹¹¹^ORCID,Sztupinszki Zsofia²¹²^ORCID,Samant Amruta¹,Nassar Amin¹³^ORCID,Bekele Raie T.¹⁵,Hanlon Timothy¹,Valentine Henkel¹⁴,Epstein Ilana¹⁰,Sharma Bijaya¹⁵,Felt Kristen¹⁵,Abbosh Philip¹⁴¹⁶,Wu Chin-Lee⁵¹⁷^ORCID,Efstathiou Jason A.⁵⁶^ORCID,Miyamoto David T.⁵⁶⁷^ORCID,Anderson William⁵⁸,Szallasi Zoltan²¹²¹⁸^ORCID,Mouw Kent W.¹⁵⁷¹⁹^ORCID

Affiliation:

1. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

2. Danish Cancer Institute, Copenhagen, Denmark.

3. Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

4. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA.

5. Harvard Medical School, Boston, MA, USA.

6. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

7. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

8. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA.

9. Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

10. Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

11. Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

12. Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.

13. Department of Hematology/Oncology, Yale New Haven Hospital, New Haven, CT, USA.

14. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

15. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

16. Albert Einstein Medical Center, Philadelphia, PA, USA.

17. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

18. 2nd Department of Pathology, SE NAP, Brain Metastasis Research Group and Department of Bioinformatics, Semmelweis University, Budapest, Hungary.

19. Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adg2263

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