Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells

Marcia A Ciccone; Crystal L Adams; Charles Bowen; Teena Thakur; Charité Ricker; Julie O Culver; Asaf Maoz; Marilena Melas; Gregory E Idos; Anand D Jeyasekharan; Koji Matsuo; Lynda D Roman; Stephen B Gruber; Kevin J McDonnell

doi:10.1016/j.ygyno.2020.09.040

Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells

Gynecol Oncol. 2020 Dec;159(3):869-876. doi: 10.1016/j.ygyno.2020.09.040. Epub 2020 Oct 5.

Authors

Affiliations

¹ USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: marcia.ciccone@med.usc.edu.
² USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, MD Anderson Cancer Center, Houston, TX, USA.
⁴ Cancer Science Institute of Singapore, National University of Singapore, Singapore.
⁵ USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
⁷ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
⁸ Department of Internal Medicine, Division of Gastroenterology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
⁹ Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, and Beckman Research Institute, Duarte, CA, USA; Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.

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: BRIP1; Genetic predisposition to cancer; Ovarian cancer; PARP inhibitor; Platinum therapeutics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
BRCA1 Protein / genetics
CHO Cells
Carboplatin / pharmacology
Carboplatin / therapeutic use
Cell Proliferation / drug effects
Cell Proliferation / genetics
Cell Survival / drug effects
Cell Survival / genetics
Cisplatin / pharmacology
Cisplatin / therapeutic use
Cricetulus
Drug Synergism
Fanconi Anemia Complementation Group Proteins / deficiency
Fanconi Anemia Complementation Group Proteins / genetics*
Female
Humans
Molecular Targeted Therapy / methods
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / pathology
Phthalazines / pharmacology
Phthalazines / therapeutic use
Piperazines / pharmacology
Piperazines / therapeutic use
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Precision Medicine / methods
RNA Helicases / deficiency
RNA Helicases / genetics*
Recombinational DNA Repair / drug effects
Synthetic Lethal Mutations / drug effects

Substances

BRCA1 Protein
BRCA1 protein, human
Fanconi Anemia Complementation Group Proteins
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Carboplatin
BRIP1 protein, human
RNA Helicases
Cisplatin
olaparib

Grants and funding

R01 CA197350/CA/NCI NIH HHS/United States