ATM protein is deficient in over 40% of lung adenocarcinomas

// Liza C. Villaruz 1, * , Helen Jones 2, * , Sanja Dacic 3 , Shira Abberbock 1 , Brenda F. Kurland 1, 4 , Laura P. Stabile 5 , Jill M. Siegfried 6 , Thomas P. Conrads 7 , Neil R. Smith 2 , Mark J. O’Connor 2 , Andrew J. Pierce 2 , Christopher J. Bakkenist 5, 8 1 University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 2 Astrazeneca, Cambridge, United Kingdom 3 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 4 Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA 5 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 6 Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA 7 Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA 8 Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA * Co-first authors Correspondence to: Christopher J. Bakkenist, email: bakkenistcj@upmc.edu Keywords: ataxia telangiectasia mutated (ATM), ATM and Rad-3-related (ATR), lung adenocarcinoma, non-small cell lung cancer (NSCLC) Received: March 21, 2016 Accepted: April 28, 2016 Published: June 01, 2016 ABSTRACT Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1 st -line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000’s of patients with ATM-deficient lung adenocarcinoma every year.