PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells

摘要

Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer (NSCLC) despite poor response rates and limited response duration. It has been reported that tumor expression of excision repair cross-complementation group 1 (ERCC1), a key component in nucleotide excision repair, may correlate with clinical response to platinum agents. We found that most primary lung tumor specimens demonstrated a stronger protein expression of poly (adenosine diphosphate ribose) polymerases 1 (PARP1) than their normal counterparts. Therefore, we hypothesized that combining PARP inhibition with platinum compounds may be an approach to improve platinum-based therapy for NSCLC. Drug combination experiments revealed that two distinct PARP inhibitors, olaparib and veliparib, not only potentiated the cell killing by cisplatin but also conferred cytotoxicity as a single agent specifically in ERCC1-low HCC827 and PC9 but not in ERCC1-high A549 and H157 lung cancer cells. Moreover, small interfering RNA knockdown of ERCC1 in A549 and H157 cells increased their sensitivities to both cisplatin and olaparib in a synergistic manner in our model. Furthermore, mechanistic studies indicated that combined PARP inhibitor and cisplatin could lead to sustained DNA double-strand breaks, prolonged G. 2/M cell cycle arrest with distinct activation of checkpoint kinase 1 signaling and more pronounced apoptosis preferentially in lung cancer cells with low ERCC1 expression. Collectively, these data suggest that there is a synergistic relationship between PARP inhibition and low ERCC1 expression in NSCLC that could be exploited for novel therapeutic approaches in lung cancer therapy based on tumor ERCC1 expression.