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

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, Atmdeficient 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. Ó2017 AACR.

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

“…In the context of KRAS -driven lung adenocarcinoma and PDAC, 2 recent preclinical in vivo studies have highlighted the potential importance of ATR inhibitors. The ATR inhibitor VE-822 displayed selective cytotoxicity in Tp53 -deficient Kras -driven lung adenocarcinoma cells and tumors that lacked Atm expression, whereas the Atm -proficient controls were significantly more resistant [81]. The effects observed with VE-822 were similar to those observed with olaparib, which was employed as a control in these studies [81].…”

“…Thus, it has been speculated that it is the HR defect in BRCA1/2 -mutated cancer cells that confers sensitivity to PARP inhibition [73,74]. In line with this concept, further experiments have shown that PARP inhibition is indeed selectively toxic in cancer cells that harbor aberrations in additional HR genes, such as ATM , RAD51 , RAD54 , DSS1 , RPA1 , NBN , ATR , CHEK1 , CHEK2 , FANCD2 , FANCA and FANCC [77,78,79,80,81]. Given that several critical phenotypes that are associated with BRCA1 or BRCA2 deficiency are also detectable in situations where no germline BRCA1/2 mutation can be detected, the term ‘BRCA-ness' has been coined.…”

“…In addition to PARP inhibitors, HR-defective cancer cells were recently shown to display actionable sensitivities against inhibitors to ATR and DNA-PKcs [78,80,81,86,87,88,89]. DNA-PKcs is a central component of the NHEJ pathway [49].…”

“…The ATR inhibitor VE-822 displayed selective cytotoxicity in Tp53 -deficient Kras -driven lung adenocarcinoma cells and tumors that lacked Atm expression, whereas the Atm -proficient controls were significantly more resistant [81]. The effects observed with VE-822 were similar to those observed with olaparib, which was employed as a control in these studies [81]. The preclinical efficacy of VE-822 was also assessed in Atm -proficient and -deficient models of Kras -driven PDAC [78].…”

“…These include, but are probably not limited to, a substantially increased PARP inhibitor sensitivity in HR-defective settings, compared to HR-proficient cells and tumors (fig. 1) [73,74,76,77,78,79,80,81]. First steps of clinical validation have demonstrated the complexity of this disease in BRCA mutation carriers strongly depending on the treatment context [94,95].…”