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

Anna Schmitt,Gero Knittel,Tsun-Po Yang,Michael Nowak,Martin Peifer,Uschi Leeser,Hans Christian Reinhardt,Sven Perner,Daniela Welcker,Julie George,Reinhard Büttner

doi:10.1158/0008-5472.can-16-3398

Abstract

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040-56. ©2017 AACR.

Highlights

Lung cancer is the most common cancer entity after nonmelanocytic skin cancer, and lung cancer–related deaths surpass those from any other neoplastic disease worldwide [1]
KRAS-mutant lung adenocarcinomas remain a clinically challenging subentity, as no effective targeted single-agent or combination regimens are available in the clinical setting
Current first-line regimens for the treatment of stage IV KRASmutant lung adenocarcinomas consist of platinum-based combination chemotherapy together with a VEGF-blocking antibody

Summary

Introduction

Lung cancer is the most common cancer entity after nonmelanocytic skin cancer, and lung cancer–related deaths surpass those from any other neoplastic disease worldwide [1]. The most prominent example in this regard is oncogenically mutated KRAS, which occurs in approximately 32% of lung adenocarcinomas and for which no direct targeting approaches have been clinically developed, far [5]. KRAS mutations were recently shown to cocluster with mutations affecting the p53 response in lung adenocarcinoma [6]. 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]

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Results

Conclusion