Inhibition of succinate dehydrogenase sensitizes cyclin E‐driven ovarian cancer to CDK inhibition

Abstract

AbstractAim: High‐grade serous ovarian cancer (HGS‐OvCa) is characterized by widespread CCNE1 amplification. Current treatments lack specificity to target Cyclin E‐driven OvCa. Methods: By in silico analysis of the TCGA OvCa dataset we searched association between genes involved in glucose metabolism and cell cycle control. Metabolic shift was studied in Cyclin E‐driven OvCa cells treated with CDK inhibition (CDKi). Genetic and pharmaceutical inhibition of succinate dehydrogenase (SDH) was tested in combination with CDKi. Results: OvCa patients with CCNE1 amplification could be divided by concomitant SDHA amplification. A2780 OvCa cells were similar to the Cyclin E‐driven and SDHA neutral genotype. CDKi in A2780 cells using Dinaciclib resulted in compensatory enhancement of tricarboxylicacid cycle (TCA) cycle activity. Combined blockade of CDK and SDH, both genetically and pharmaceutically, showed synergy and resulted in inhibited proliferation, migration, invasion and migration in A2780 cells. The combined inhibition did not further alter cell cycle population, but induced apoptosis of A2780 cells. Conclusion: Cyclin E‐driven OvCa cells appeared addicted to glucose metabolism via TCA. Combined CDKi with modalities targeting TCA, like SDHA inhibition showed promising effects for this genotype. © 2016 BioFactors, 42(2):171–178, 2016