Targeting the RhoGTPase/ROCK pathway for the treatment of VHL/HIF pathway-driven cancers

Abstract

The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. We recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation. Increased expression and activity of both HIFs and ROCK1 occurs in many types of cancer supporting the potential therapeutic role of ROCK inhibitors beyond CC-RCC. We also discuss future research required to establish prognostic markers to predict tumor response to ROCK inhibitors.

Keywords: Clear Cell Renal Cell Carcinoma; HIF; ROCK1; Rho; VHL; synthetic lethality.

Figure 1.

Overview of VHL/HIF and Rho/ROCK signaling pathways. VHL, left, is a part of an E3 ubiquitin ligase complex that targets HIF-1α and HIF-2α for degradation. The loss of VHL stabilizes HIFs, leading to elevated expression of a multitude of HIF-target genes, involved in angiogenesis, migration, invasion, glycolysis, etc. ROCK signaling, right, is dependent on activation by RhoGTPases that bind to ROCK1 and ROCK2. ROCK family kinases are major regulators of actin organization within the cell controlling actin filament stabilization, actomyosin contraction, actin cytoskeleton rearrangements, microtubule stabilization, etc. The combination of VHL loss leading to HIF overactivation and Rho/ROCK pathway inhibition triggers synthetic lethality.