ATM protein is deficient in over 40% of lung adenocarcinomas

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 1st-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.

ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma

“…Only very recently, immune checkpoint-blocking antibodies are entering the first-line setting in selected patient populations. To approach these difficult to treat KRAS-mutant tumors, we initially analyzed publicly available cancer genome sequencing data to ask whether we could identify cooccurring genetic aberrations (7). Consistent with previously published data (3), we found that protein-damaging TP53 mutations, MDM2 amplifications, and CDKN2A alterations are frequently detected in KRASmutant lung adenocarcinomas (Fig.…”

“…These data suggest that an impaired DNA damage response maybe selected in KRASmutant lung adenocarcinoma. In line with this observation, it was recently shown that approximately 40% of human lung adenocarcinomas lack ATM protein expression (7).…”

Phase I study of veliparib in combination with gemcitabine

“…In this phase I study, the toxicity profile of veliparib in combination with gemcitabine is consistent with what is typically observed with gemcitabine monotherapy, with myelosuppression (leukopenia, granulocytopenia, thrombocytopenia, anemia) and nausea and vomiting being the most frequent adverse events [21,22]. Liver enzyme elevation, commonly reported with gemcitabine therapy, was also observed.…”

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

“…However, analysis of ATM mutations in Ataxia Telangiectasia, a cancer predisposition syndrome caused by loss or inactivation of both copies of the ATM gene 46 has shown that many mis-sense mutations result in protein truncation 47 . Indeed, immunohistochemistry of ATM protein expression in lung adenocarcinoma revealed that over 40% had low protein expression, despite only 10% showing gene mutation 48 . In addition, ATM promoter methylation has been shown to lead to silencing in some cancer cells 49,50 .…”