(UroToday.com) ATM (ataxia-telangiectasia mutated) is a kinase that plays a central role in the cellular response to DNA damage. A subset of bladder tumors harbor alterations in ATM, and several studies have demonstrated that tumors with alterations in ATM or other DNA damage repair genes have increased sensitivity to DNA damaging agents1 and/or immunotherapeutic (anti-PD1/PD-L1) agents.2 However, the functional contribution of ATM alterations to these clinical associations has not yet been studied in detail.
In this study, Mouw and colleagues first characterized classes of ATM alterations across several large bladder cancer cohorts. They then deleted ATM in multiple mouse and human bladder cell lines and measured the impact on sensitivity to bladder cancer therapeutics in vitro and in vivo. Comprehensive immunogenomic profiling in ATM-intact and ATM-deleted syngeneic models were then performed. In addition, the investigators also developed and optimized an ATM immunohistochemistry (IHC) assay, and applied this assay to a cohort of bladder cancer cases.
They correlated ATM mutation status in these patients to IHC patterns, and clinical outcomes following treatment with chemotherapy and/or immunotherapy. 
The apparent frequency of ATM alterations in bladder cancer cohorts depends strongly on the specific criteria used to nominate alterations. Deleting ATM in bladder cell lines is sufficient to increase sensitivity to direct DNA damaging agents such as cisplatin and radiation as well as DNA repair targeted agents such as PARP and ATR inhibitors. ATM deletion confers modest changes to the immune microenvironment and anti-PD1 sensitivity in syngeneic mouse models. ATM alteration classes are strongly associated with IHC staining patterns: tumors with truncating ATM alterations frequently exhibit loss of ATM staining by IHC whereas ATM loss by IHC is uncommon among tumors with missense or no mutations. Response to cisplatin-based chemotherapy was strongly correlated with IHC staining patterns.
Presented by: Kent Mouw, MD, PhD, Dana-Farber Cancer Institute
Written by: Roger Li, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain
References:
- Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 2014;4(10):1140-1153.
- Teo MY, Seier K, Ostrovnaya I, et al. Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers. J Clin Oncol. 2018;36(17):1685-1694.