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Updated: Mar 17, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib
Margaret E Whicker1, Z Ping Lin2, Ruth Hanna3
1Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA. margaret.whicker@yale.edu.
Background:
Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer. This study examines the differential effects of AKT inhibition with cisplatin and olaparib therapy in BRCA1/2-deficient versus wild-type EOC.
Methods:
PEO1, a chemosensitive BRCA2-mutant serous ovarian adenocarcinoma, and PEO4, a reverted BRCA2-proficient line from the same patient after the development of chemotherapeutic resistance, were primarily used for the study. In PEO1, MK-2206 demonstrated moderate to strong synergism with cisplatin and olaparib at all doses, while demonstrating antagonism at all doses in PEO4.
Results:
Baseline phospho-AKT activity in untreated cells was upregulated in both BRCA1- and 2-deficient cell lines. MK-2206 prevented cisplatin- and olaparib-induced AKT activation in the BRCA2-deficient PEO1 cells. We propose that BRCA-deficient EOC cells upregulate baseline AKT activity to enhance survival in the absence of HR. Higher AKT activity is also required to withstand cytotoxic agent-induced DNA damage, leading to strong synergism between MK-2206 and cisplatin or olaparib therapy in BRCA-deficient cells.
Conclusions:
MK-2206 shows promise as a chemosensitization agent in BRCA-deficient EOC and merits clinical investigation in this patient population.
Insights
AKT inhibition with MK-2206 synergizes with platinum and olaparib in BRCA-deficient ovarian cancer. This combination therapy shows promise for treating platinum-resistant epithelial ovarian cancer (EOC) in patients with BRCA mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Platinum resistance is a significant challenge in epithelial ovarian cancer (EOC) treatment.
- The AKT pathway activation correlates with platinum resistance, while AKT inhibition sensitizes resistant cells.
- BRCA-mutant EOC patients show better response to platinum and olaparib due to homologous recombination (HR) repair defects.
Purpose of the Study:
- To investigate the differential effects of AKT inhibition combined with cisplatin and olaparib in BRCA1/2-deficient versus wild-type EOC.
- To evaluate MK-2206, an AKT inhibitor, as a chemosensitization agent in EOC models.
Main Methods:
- Utilized PEO1 (BRCA2-mutant, chemosensitive) and PEO4 (BRCA2-proficient, chemoresistant) ovarian cancer cell lines.
- Assessed the synergistic, additive, or antagonistic effects of MK-2206 with cisplatin and olaparib.
- Measured baseline and drug-induced AKT phosphorylation levels.
Main Results:
- MK-2206 exhibited moderate to strong synergism with cisplatin and olaparib in BRCA2-deficient PEO1 cells.
- Conversely, MK-2206 showed antagonism with these agents in BRCA2-proficient PEO4 cells.
- BRCA-deficient cells displayed upregulated baseline phospho-AKT, which was reduced by MK-2206, suggesting a role in survival and DNA damage resistance.
Conclusions:
- AKT inhibition via MK-2206 demonstrates significant chemosensitization potential in BRCA-deficient EOC.
- The combination of MK-2206 with cisplatin or olaparib warrants further clinical investigation for BRCA-mutant EOC patients.
