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.

Synergistic Effect of Olaparib with Combination of Cisplatin on PTEN-Deficient Lung Cancer Cells

“…In recent years, our understanding of how to treat NSCLCs has undergone a paradigm shift by the identification of EGFR mutations (42,43) and EML4-ALK translocation (44). In BRCA1-deficient lung cancer, PARP inhibition induced BAX/BAKindependent synthetic lethality (45). Knowledge of the status of multiple DNA repair profiling of patients and may discriminate patients with likelihood to respond to PARP inhibitors.…”

Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

“…Immunofluorescent cytochemistry was carried out as previously described (Paul et al., 2011) using anti γ-H2AX, (05–636, Millipore), BCLAF1 (BTF 608A, Bethyl Labs), and U2AF65 (MC3, Santa Cruz) antibodies.…”

Identification and Comparison of Aberrant Key Regulatory Networks in Breast, Colon, Liver, Lung, and Stomach Cancers through Methylome Database Analysis

“…This unique epigenome characteristic might put colon cancer farthest from breast cancer. Breast and lung cancer have many common prognostic signatures, such as hypermethylation of BRCA1 [35], SOX17 [36], [37], and TLX3.…”