RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy.

Ahlem Jebali,Nicolas Dumaz,Maxime Battistella,Céleste Lebbé

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.

Highlights

Introduction and Fabio PastorinoMalignant melanoma, a tumor arising from melanocytes, is the most aggressive form of skin cancer with a high tendency to rapidly metastasize
To confirm the inhibitory effect of JR-AB2-011 in a more physiological setting, we used cells grown as spheroids. We showed in this setting that physiological setting, we used cells grown as spheroids. We showed in this setting that the parental cells were more sensitive to a BRAF inhibitor than the mTORC2 inhibitor, but the parental cells were more sensitive to a BRAF inhibitor than the mTORC2 inhibitor, the cells resistant to the BRAF inhibitor were very sensitive to mTORC2 inhibition (Supbut the cells resistant to the BRAF inhibitor were very sensitive to mTORC2 inhibition plementary Figure S5), confirming the importance of mTORC2 in resistance to therapy
Our study focused on the role of the scaffolding protein RICTOR, a key component of mTORC2 that is required the role of the scaffolding protein RICTOR, a key component of mTORC2 that is required for mTORC2 function

Summary

Introduction

Introduction and Fabio PastorinoMalignant melanoma, a tumor arising from melanocytes, is the most aggressive form of skin cancer with a high tendency to rapidly metastasize. Recent advances in melanoma research have established the molecular oncogenic events that contribute to melanoma initiation and progression, allowing the development of targeted therapies. The discovery of BRAF mutations in 50–60% of primary melanoma has led to the development of BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib), as well as MEK inhibitors (cobimetinib, trametinib, and binimetinib), which have improved prognoses and the overall survival in patients with metastatic BRAF-mutant disease. Despite a remarkable early remission and overall improvement of patient outcome on BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy, resistance to RAF/MEK-targeted therapies invariably occurs and most patients relapse within five years of treatment [1,2,3]. In the majority of progressing melanoma, resistance occurs via the re-activation of MAPK signaling, but a proportion of resistant melanoma relies on the activation of the compensatory phosphoinositide 3-kinase (PI3K) signaling cascade [4]

Methods

Results

Conclusion