dactolisib and von-Hippel-Lindau-Disease

Loss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.

Topics: Aurora Kinase A; Carcinoma, Renal Cell; Cell Line, Tumor; Cilia; Gene Knockdown Techniques; Humans; Imidazoles; Kidney Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Quinolines; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Burden; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays