High grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, accounting for approximately 70-80% of deaths. Cyclin E1 (CCNE1) amplification is detected in up to 15% of HGSOC, and has been shown to be associated with primary treatment resistance and poor outcome. Cyclin E1 is a cell cycle regulator that partners with cyclin-dependent kinases (CDK) to signal within cells, particularly Cdk2. We aim to identify strategies to target CCNE1 amplification in HGSOC using preclinical studies, and investigate potential resistance mechanisms to these targeted agents.
We have previously demonstrated that ovarian cancer cells with CCNE1 amplification are specifically sensitive to Cdk2 inhibitors. In addition, we generated ovarian cancer cell lines that are resistant to dinaciclib, a potent Cdk2 inhibitor in advanced clinical development. In order to investigate potential drug combinations that would overcome resistance to Cdk2 inhibitors, we performed a high throughput compound screen (HTCS) of over 4,000 drugs in combination with dinaciclib. Hits were then assessed using the Chou-Talalay isobologram method to characterise the interaction for each individual drug combination. Synergistic drug combinations were then validated in drug cytotoxicity assays across additional resistant ovarian cancer cell lines to identify common resistance mechanisms.
The HTCS identified multiple compounds that were synergistic in combination with dinaciclib in Cdk2 inhibitor resistant cells. Two BH3 mimetics (pro-apoptotic compounds), ABT-737 and ABT-263 were selectively synergistic with dinaciclib in resistant cell lines. By contrast, ABT-199, a selective Bcl-2 inhibitor, was not synergistic with dinaciclib. Our findings indicate that multiple proteins in the pro-apoptotic pathway must be targeted to overcome resistance to Cdk2 inhibitors.
Results from a HTCS indicate that targeting multiple components of the apoptotic pathway using BH3 mimetics may overcome resistance to Cdk2 inhibitors in CCNE1 amplified HGSOC. Ongoing studies will provide further insights into the underlying biology of drug resistance.
Clinical trial identification
All authors have declared no conflicts of interest.