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PARP inhibition induces BAX/BAK‐independent synthetic lethality of BRCA1‐deficient non‐small cell lung cancer
Author(s) -
Paul Ian,
Savage Kienan I,
Blayney Jaine K,
Lamers Elisabeth,
Gately Kathy,
Kerr Keith,
Sheaff Michael,
Arthur Kenneth,
Richard Derek J,
Hamilton Peter W,
James Jacqueline A,
O'Byrne Kenneth J,
Harkin D Paul,
Quinn Jennifer E,
Fennell Dean A
Publication year - 2011
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2925
Subject(s) - synthetic lethality , cancer research , apoptosis , poly adp ribose polymerase , biology , olaparib , gene silencing , rna interference , small hairpin rna , mutation , lung cancer , mitochondrion , dna repair , microbiology and biotechnology , medicine , rna , genetics , gene , pathology , polymerase , gene knockdown
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. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.