Abstract 6395: VHL deficiency sensitizes CC-RCC to inhibition of small GTPases by statins

Abstract

Clear cell renal cell carcinoma (CC-RCC) type of kidney cancer has limited therapeutic options available for advanced stages. The objective of this study was to investigate statins as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. Treatment with statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Rho and Rho kinase (ROCK) inhibition by siRNAs, as well as C3-toxin (for Rho) and Y27637 (for ROCK) mimic the statin-mediated synthetic lethality effect, suggesting the involvement of Rho/ROCK pathway in the mechanism. Overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required for statin-mediated toxicity. Since both VHL and ROCK were previously reported to control mitosis fidelity, we show that mitotic catastrophe is one of the mechanisms of action of compounds targeting the Rho/ROCK pathway in VHL-deficient CC-RCC. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC.

Citation Format: Olga V. Razorenova, Jordan M. Thompson, Alejandro Alvarez, Monika K. Singha, Matthew W. Pavesic MW, Quy H. Nguyen, Luke J. Nelson, David A. Fruman. VHL deficiency sensitizes CC-RCC to inhibition of small GTPases by statins [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6395.