- •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.
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.
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.
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.
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.
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- Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419
- The BRCT domain is a phospho-protein binding domain.Science. 2003; 302: 639-642
- The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair.Nat. Genet. 2005; 37: 953
- Mutations in BRIP1 confer high risk of ovarian cancer.Nat. Genet. 2011; 43: 1104-1107
- Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc. Natl. Acad. Sci. 2011; 108: 18032-18037
- Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer.J. Natl. Cancer Inst. 2015; 107 (p. djv214-djv214)
- Latest clinical evidence and further development of PARP inhibitors in ovarian cancer.Ann. Oncol. 2018; 29: 1366-1376
- Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.N. Engl. J. Med. 2019; 381: 2416-2428
- Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.N. Engl. J. Med. 2019; 381: 2403-2415
- PARP inhibitors in epithelial ovarian cancer: state of art and perspectives of clinical research.Anticancer Res. 2016; 36: 2055-2064
- Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma.Nat. Commun. 2019; 10: 5367
- Germline variants in targeted tumor sequencing using matched normal DNA.JAMA Oncol. 2016; 2: 104-111
- BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.Mol. Oncol. 2013; 7: 567-579
- Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies.Pharmacol. Rev. 2006; 58: 621-681
- Quantitative analysis of copy number variants based on real-time LightCycler PCR.Curr. Protoc. Hum. Genet. 2014; 80 (p. Unit 7 21)
- Genetic interactions in cancer progression and treatment.Cell. 2011; 145: 30-38
- Discovery of small molecule cancer drugs: successes, challenges and opportunities.Mol. Oncol. 2012; 6: 155-176
- BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.Cell. 2001; 105: 149-160
- H2AX phosphorylation: its role in DNA damage response and cancer therapy.J. Nucleic. Acids. 2010; 2010
- Gamma-H2AX - a novel biomarker for DNA double-strand breaks.In Vivo. 2008; 22: 305-309
- Biomarkers for homologous recombination deficiency in cancer.J. Natl. Cancer Inst. 2018; 110: 704-713
- PARP inhibitors: synthetic lethality in the clinic.Science. 2017; 355: 1152-1158
- Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models.Mol. Cancer Ther. 2012; 11: 1948-1958
- Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome.Nat. Biotechnol. 2013; 31: 759-765
- Integrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615
- RECQL1 and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma.Cancer Res. 2011; 71: 4598-4607
- Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase.Mol. Cell. Biol. 2007; 27: 6733-6741
- Cloning and characterization of Chinese hamster p53 cDNA.Gene. 1997; 184: 177-183
- The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair.Nat. Genet. 2005; 37: 953-957
- Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921
- Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration.J. Clin. Oncol. 2020; (Online ahead of print)JCO2001035
- Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others.Nat. Rev. Clin. Oncol. 2018; 15: 13-30
- ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.Clin. Cancer Res. 2007; 13: 2728-2737
- High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 17079-17084
- Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.Lancet Oncol. 2015; 16: 87-97
- Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N. Engl. J. Med. 2018; 379: 2495-2505
- A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation — An NRG Oncology/Gynecologic Oncology Group study.Gynecol. Oncol. 2015; 137: 386-391
- Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.Cancer Discov. 2012; 2: 1048-1063
- Phase I study of oral BKM120 and oral olaparib for high-grade serous ovarian cancer (HGSC) or triple-negative breast cancer (TNBC).J. Clin. Oncol. 2014; 32 (p. 2510–2510)
- PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression.Clin. Cancer Res. 2017; 23: 3711-3720
Published online: October 05, 2020
Accepted: September 23, 2020
Received: May 8, 2020
© 2020 Elsevier Inc. All rights reserved.