Microtubule dynamics is a therapeutic vulnerability in VHL-deficient renal cell carcinoma.

Von Hippel-Lindau (VHL) is a tumor suppressor frequently mutated in renal cell carcinoma (RCC) and its loss has been considered as a target for therapeutic exploitation. In an effort to identify therapeutic vulnerabilities in VHL-deficient RCC, we found that SKPin C1, a SKP2 inhibitor, exhibited synthetic lethal effects on VHL-deficient RCC cells. SKPin C1 selectively disrupted spindle assembly in VHL-deficient RCC, leading to the induction of mitotic arrest and death. These effects were independent of its inhibitory action on SKP2. Our in-depth biochemical and molecular interaction studies reveal that SKPin C1 binds to tubulin and inhibits microtubule polymerization. Interestingly, anti-microtubule effect of SKPin C1 was much more pronounced in VHL-deficient RCC cells. Further mechanistic studies on the synthetic lethality reveal that VHL loss alters microtubule dynamics in cells, promoting microtubule growth speed while reducing stability. Treatment of VHL-deficient RCC cells with SKPin C1 or other microtubule destabilizers strongly suppressed microtubule growth and reduced the levels of GTP-tubulin and acetylated microtubules, resulting in selective vulnerability in VHL-deficient RCC. Taken together, our study suggests that microtubule dynamics is a therapeutic vulnerability in VHL-deficient RCC and provides a rationale for the combination treatment of VHL-deficient RCC with anti-microtubule agents and RCC targeted therapies.