title: PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells.
abstract: 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 G2/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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Cheng
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Alain
authors.initials: A
authors.lastname: Borczuk
authors.forename: Charles A
authors.initials: CA
authors.lastname: Powell
authors.forename: Adayabalam S
authors.initials: AS
authors.lastname: Balajee
authors.forename: Howard B
authors.initials: HB
authors.lastname: Lieberman
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D004720:Endonucleases / Q000096:biosynthesis* / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; C531550:olaparib