Abstract

Epithelial ovarian cancer, especially high-grade serous ovarian cancer (HGSOC) remains deadliest gynecological malignancy due to lack of early-detection biomarkers and chemoresistance. Protein kinase D (PKD1-3), a member of diacylglycerol (DAG)-targeting, Ca++-Calmodulin family of serine/threonine kinases emerged as a novel, targetable driver of HGSOC. This review synthesizes significance of currently discovered molecular mechanisms of PKD-driven carcinogenesis of the ovary, promise of CRT0066101, a highly selective, potent PKD inhibitor as excellent anti-cancer agent and critically discussed importance of unidentified PKD substrates as novel pathobiological effectors and therapeutic targets in HGSOC. Mechanistically, PKD2 and PKD3 modulated Runx2 via MAPK/ERK1/2 pathway to drive HGSOC cell proliferation, EMT, migration/invasion and regulated Aurora kinase A via ERK signalling to induce uncontrolled G2/M cell cycle transition, mitosis and highly aggressive, chemoresistant neuroendocrine transdifferentiation. Furthermore, we discussed translational potential and challenges in developing highly selective, PKD isoform-specific inhibitors, preclinical and clinical pipelines to assess therapeutic efficacy of PKD inhibitors in combination with other regimens such as PARP and folate receptor antagonists and novel tumor cell-targeting nanotheranostics approaches to deliver nanoparticulate drugs, ASOs or siRNAs directed against PKD for improved patient outcomes.