Abstract 4690: PARP inhibition increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancers

Abstract

Abstract Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer (NSCLC) but nevertheless response rates are disappointing and response duration is limited. Tumor expression of ERCC1, a key enzyme in nucleotide excision repair, may correlate with clinical response to platinum agents. Inhibition of poly(ADP-ribose) polymerases (PARPs), enzymes essential for base excision repair, enhances platinum sensitivity in BRCA-associated breast and ovarian cancers. We hypothesized that combining PARP inhibition with platinum compounds for tumors with low ERCC1 expression, may be an approach to optimize platinum-based therapy for NSCLC. In primary lung tumor specimens and NSCLC cell lines, PARP1 was found to be a mainly nuclear protein with higher expression in tumor cells as compared to normal counterparts. Drug combination experiments revealed that olaparib (PARP inhibitor) selectively synergized with cisplatin in ERCC1-low HCC827 and PC9 but not in ERCC1-high A549 and H157 lung cancer cells. Similar data were obtained with an alternative PARP inhibitor, veliparib (ABT-888). Moreover, siRNA-mediated knockdown of ERCC1 in ERCC1-high A549 and H157 cells increased sensitivities of both cisplatin and olaparib. Mechanistic studies further indicated that PARP inhibition alone or in combination with cisplatin led to cell cycle arrest in the G2/M phase, via activation of the DNA damage checkpoint pathways involving γH2AX, checkpoint kinase 1 and p53. These data suggest that there is a synthetically lethal relationship between PARP inhibition and ERCC1 loss in NSCLC that could be exploited for novel therapeutic approaches in lung cancer therapy based on tumor ERCC1 expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4690. doi:1538-7445.AM2012-4690