Highlights
- •BRIP1 deficiency decreases cell proliferation, impairs homologous recombination, and interferes with DNA repair in vitro.
- •Pathogenic BRIP1 alterations increased susceptibility to platinum agents but not to olaparib monotherapy.
- •The combination of platinum and olaparib therapy resulted in synergistic lethality in cells with expressing altered BRIP1.
- •We provide pre-clinical support for use of PARP-inhibitors in the setting of ovarian cancer patients with BRIP1 mutations.
- •We show pre-clinical evidence for PARP-inhibitor maintenance after platinum treatment in BRIP1-mutated ovarian cancer.
Abstract
Objective
Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting
protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic
lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between
BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated
the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity.
Methods
We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient
BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed
cellular proliferation and survival; we calculated inhibitory concentrations and combination
and reduction drug indices.
Results
BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises
DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure
alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically
attenuates cellular survival, consistent with synthetic lethality.
Conclusions
BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality
when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this
lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation
supports consideration of the use of a platinum agent/PARPi combination in ovarian
cancers depending upon genetic profile and genomic background.
Keywords
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Article info
Publication history
Published online: October 05, 2020
Accepted:
September 23,
2020
Received:
May 8,
2020
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
