RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy

  • Biomedicines. 2021 Oct 19;9(10):1498. doi: 10.3390/biomedicines9101498.
Ahlem Jebali  1  2 ,  Maxime Battistella  1  2  3 ,  Céleste Lebbé  1  2  4 ,  Nicolas Dumaz  1  2
Affiliations
  • 1. INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.
  • 2. Institut de Recherche Saint Louis (IRSL), Université de Paris, F-75010 Paris, France.
  • 3. Pathology Department, Saint-Louis Hospital, AP-HP, F-75010 Paris, France.
  • 4. Dermatology Department, Saint-Louis Hospital, AP-HP, F-75010 Paris, France.
PMID: 34680615 DOI: 10.3390/biomedicines9101498
Abstract

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.

Keywords
BRAF; BRAF inhibitors; mTOR; mTOR inhibitors; mTORC2; melanoma; resistance.
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