Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete response rate. In this study we evaluated a cyclin-dependent kinase inhibitor, Dinaciclib, as a potential new targeted therapeutic for CC-RCC. In vitro , Dinaciclib showed anti-proliferative and pro-apoptotic effects on CC-RCC cell lines in Cell Titer Glo, Crystal Violet, FACS-based cell cycle analysis, and TUNEL assays. Additionally, these responses were accompanied by a reduction in phospho-Rb and pro-survival MCL-1 cell signaling responses, as well as the induction of caspase 3 and PARP cleavage. In vivo , Dinaciclib efficiently inhibited primary tumor growth in an orthotopic, patient-derived xenograft-based CC-RCC mouse model. Importantly, Dinaciclib targeted both CD105 + cancer stem cells (CSCs) and CD105 − non-CSCs in vivo . Moreover, normal cell lines, as well as a CC-RCC cell line with re-expressed von-Hippel Lindau ( VHL ) tumor suppressor gene, were protected from Dinaciclib-induced cytotoxicity when not actively dividing, indicating an effective therapeutic window due to synthetic lethality of Dinaciclib treatment with VHL loss. Thus, Dinaciclib represents a novel potential therapeutic for CC-RCC.

Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)

“…However, identification of additional predictive biomarkers is key to determine the treatment options according to the RCC molecular characteristics (132). Drugs that promote HR repair defects in tumor cells (i.e., PI3K inhibitors, cyclin-dependent kinase inhibitors) may increase sensitivity to PARPis (133)(134)(135)(136). As a specific polymerase θ inhibitor, novobiocin is combined with PARPi in treatment of HR-deficient tumors, as well in tumors that have acquired PARPi resistance (137).…”