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.
Highlights
ATM and ATR are serine/ threonine protein kinases that phosphorylate a broad and overlapping catalogue of several thousand substrates that collectively impact cell cycle progression, DNA replication and repair, transcription, translation and metabolism [1,2,3].Above poorly defined thresholds of DNA damage, ATM and ATR kinase signaling can lead to either apoptosis or senescence [1,2,3]
ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATMdeficient lung cancer
We report the validation of a commercial antibody 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
Summary
ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad 3-related) are serine/ threonine protein kinases that phosphorylate a broad and overlapping catalogue of several thousand substrates that collectively impact cell cycle progression, DNA replication and repair, transcription, translation and metabolism [1,2,3].Above poorly defined thresholds of DNA damage, ATM and ATR kinase signaling can lead to either apoptosis or senescence [1,2,3]. ATM is activated within seconds to minutes of exposure to ionizing radiation (IR) and other agents that induce DNA double-strand breaks (DSBs) [4,5,6,7]. ATR is activated within minutes to hours of exposure to agents that induce stalled and collapsed replication forks and at DSBs after end-resection [8]. Mice that express no ATM protein are viable, have an increased incidence of lymphoid malignancies and are radiosensitive, but show no signs of neurodegeneration [11, 12]. Expression of ATM kinase-inactive protein causes early embryonic lethality in mice [13, 14]. Deletion of ATR causes early embryonic lethality in mice [15]. Acquired ATM loss may be exploited for clinical benefit as pharmacologic ATR kinase inhibitors including VE821, VE-822/VX970 and AZD6738 synergize with cisplatin to kill ATM-deficient cancer cells in vitro and to resolve xenograft models of ATM-deficient lung cancer in vivo [16,17,18,19]
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