RICTOR/mTORC2 downregulation in BRAF V600E melanoma cells promotes resistance to BRAF/MEK inhibition.

Autor: Ponzone L; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Audrito V; Department of Science and Technological Innovation, University of Piemonte Orientale, Alessandria, 15121, Italy., Landi C; Functional Proteomic Section, Department of Life Sciences, University of Siena, Siena, 53100, Italy., Moiso E; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA., Levra Levron C; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Life Sciences and Systems Biology, University of Turin, Turin, 10126, Italy., Ferrua S; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Savino A; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Vitale N; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Gasparrini M; Department of Agriculture, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy., Avalle L; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy.; Department of Science and Technological Innovation, University of Piemonte Orientale, Alessandria, 15121, Italy., Vantaggiato L; Functional Proteomic Section, Department of Life Sciences, University of Siena, Siena, 53100, Italy., Shaba E; Functional Proteomic Section, Department of Life Sciences, University of Siena, Siena, 53100, Italy., Tassone B; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy.; Department of Personal Care, dsm-firmenich, Kaiseraugst, 4303, Switzerland., Saoncella S; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Orso F; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Viavattene D; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Marina E; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Fiorilla I; Department of Science and Technological Innovation, University of Piemonte Orientale, Alessandria, 15121, Italy., Burrone G; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy.; Department of Clinical and Biological Sciences, University of Turin, Turin, 10124, Italy., Abili Y; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy.; GenomeUp, Rome, 00144, Italy., Altruda F; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Bini L; Functional Proteomic Section, Department of Life Sciences, University of Siena, Siena, 53100, Italy., Deaglio S; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Medical Sciences, University of Turin, Turin, 10124, Italy., Defilippi P; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Menga A; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Poli V; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Porporato PE; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Provero P; Neuroscience Department 'Rita Levi Montalcini', University of Turin, Turin, 10126, Italy., Raffaelli N; Department of Agriculture, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy., Riganti C; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Oncology, University of Turin, Turin, 10124, Italy., Taverna D; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Cavallo F; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy., Calautti E; Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy. vincenzo.calautti@unito.it.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, 10126, Italy. vincenzo.calautti@unito.it.
Jazyk: angličtina
Zdroj: Molecular cancer [Mol Cancer] 2024 May 16; Vol. 23 (1), pp. 105. Date of Electronic Publication: 2024 May 16.
DOI: 10.1186/s12943-024-02010-1
Abstrakt: Background: The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM.
Methods: After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF V600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo.
Results: Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAF V600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi.
Conclusions: Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAF V600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.
(© 2024. The Author(s).)
Databáze: MEDLINE
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