Cancer Res 2017 06 31;77(11):3040-3056. Epub 2017 Mar 31.
Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
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 deletion in mouse models of -mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, -deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, -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. 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 mutations, particularly given their impact on PARP1 and ATR inhibitors. .