Targeting Mediator Kinase Cyclin-Dependent Kinases 8/19 Potentiates Chemotherapeutic Responses, Reverses Tumor Growth, and Prolongs Survival from Ovarian Clear Cell Carcinoma.

BACKGROUND/OBJECTIVE: Ovarian clear cell carcinomas (OCCCs) are a rare histological subtype of epithelial ovarian cancer characterized by resistance to platinum-based therapy. CDK8/19, a component of the regulatory CDK module associated with Mediator complex, has been implicated in transcriptional reprogramming and drug resistance in various solid tumors. Our study aimed to investigate the therapeutic potential of CDK8/19 kinase inhibition using selective inhibitors SNX631 and SNX631-6 in OCCC treatment, both as monotherapy and in combination with standard chemotherapeutics. METHODS: CDK8 and Ki67 levels were evaluated via immunohistochemistry in benign, primary, and metastatic ovarian cancer tissues. The efficacy of SNX631 alone and in combination with cisplatin or paclitaxel was assessed in OCCC cell lines (ES-2, TOV-21-G, RMG-1). In vivo evaluation utilized xenograft models with subcutaneous and intraperitoneal delivery of the OCCC ES2 cells and oral delivery of SNX631-6, with the monitoring of tumor growth, metastatic spread, and survival. RESULTS: CDK8 protein levels were elevated in OC tissues, particularly in OCCC primary and metastatic lesions compared to benign tissue. While CDK8/19 inhibition showed limited effects on in vitro cell proliferation, SNX631-6 demonstrated significant antitumor and anti-metastatic activity in vivo. Notably, SNX631-6 enhanced the efficacy of cisplatin, substantially inhibiting tumor growth and extending overall survival. CONCLUSIONS: Therapeutically achievable doses of CDK8/19 inhibitors may provide clinical benefit for OCCC patients by inhibiting tumor growth and reversing platinum resistance, potentially addressing a critical treatment challenge in this rare ovarian cancer subtype.