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. 2017 Jun 1;77(11):3040-3056.
doi: 10.1158/0008-5472.CAN-16-3398. Epub 2017 Mar 31.

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

Anna Schmitt  1   2 , Gero Knittel  3   2 , Daniela Welcker  3   2 , Tsun-Po Yang  4   5 , Julie George  4 , Michael Nowak  6 , Uschi Leeser  3   2 , Reinhard Büttner  7 , Sven Perner  8 , Martin Peifer  4   5 , Hans Christian Reinhardt  1   2   5
Affiliations

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

Anna Schmitt et al. Cancer Res. .

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.

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