title: PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer.
abstract: Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Paul
authors.forename: Kienan I
authors.initials: KI
authors.lastname: Savage
authors.forename: Jaine K
authors.initials: JK
authors.lastname: Blayney
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lamers
authors.forename: Kathy
authors.initials: K
authors.lastname: Gately
authors.forename: Keith
authors.initials: K
authors.lastname: Kerr
authors.forename: Michael
authors.initials: M
authors.lastname: Sheaff
authors.forename: Kenneth
authors.initials: K
authors.lastname: Arthur
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hamilton
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: James
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Quinn
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin