title: Reversing Platinum Resistance in High-Grade Serous Ovarian Carcinoma: Targeting BRCA and the Homologous Recombination System.
abstract: Resistance to platinum chemotherapy is one of the main factors driving ovarian cancer mortality, and overcoming platinum resistance is considered one of the greatest challenges in ovarian cancer research. Genetic and functional evidence points to the homologous recombination (HR) DNA repair system, and BRCA1 and BRCA2 in particular, as main determinants of response to platinum therapy. BRCA-mutant ovarian cancers are especially sensitive to platinum, associated with better survival, and amenable to poly ADP ribose polymerase inhibitor treatment. Here, we discuss a therapeutic concept that seeks to disrupt HR capacity via targeting of BRCA1 and BRCA2 functionality in order to reverse platinum resistance in BRCA-proficient high-grade serous ovarian cancers (HGSOC). We review the molecular signaling pathways that converge on BRCA1 and BRCA2, their activation status in ovarian cancer, and therapeutic options to modulate BRCA function. Several recent publications demonstrate efficient chemosensitization of BRCA-proficient cancers by combining targeted therapy with standard platinum-based agents. Due to its inherent genomic heterogeneity, molecularly defined subgroups of HGSOC may require different approaches. We seek to provide an overview of available agents and their potential use to reverse platinum resistance by inhibiting the HR system, either directly or indirectly, by targeting oncogenic activators of HR.
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, CA , USA ; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: W Ruprecht
authors.initials: WR
authors.lastname: Wiedemeyer
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, CA , USA ; Graduate Program in Biomedical Sciences and Translational Medicine, Cedars-Sinai Medical Center , Los Angeles, CA , USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Beach
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, CA , USA ; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
keywords: BRCA1; BRCA2; cyclin E1; cyclin-dependent kinase inhibitors; cyclin-dependent kinases; high-grade serous ovarian cancer; homologous recombination; platinum resistance