RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy

The network defined by phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) plays a major role in melanoma oncogenesis and has been implicated in BRaf Inhibitor resistance. The central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently begun to be unraveled. In the present study, we assessed the role of mTORC2/RICTOR in BRAF-mutated melanomas and their resistance to BRaf inhibition. We showed that RICTOR was significantly overexpressed in melanoma and associated with bad prognoses. RICTOR overexpression stimulated melanoma-initiating cells (MICs) with 'stemness' properties. We also showed that RICTOR contributed to melanoma resistance to BRaf inhibitors and rendered the cells very sensitive to mTORC2 inhibition. We highlighted a connection between mTORC2/RICTOR and STAT3 in resistant cells and revealed an interaction between Ras and RICTOR in resistant melanoma, which, when disrupted, impeded the proliferation of resistant cells. Therefore, as a key signaling node, RICTOR contributes to BRAF-dependent melanoma development and resistance to therapy and, as such, is a valuable therapeutic target in melanoma.