PXD045346

PXD045346 is an original dataset announced via ProteomeXchange.

Title	Rictor/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition
Description	Nearly 50% of cutaneous melanomas carry activating mutations on the BRAF oncogene, and the combination of BRAF- and MEK-inhibitors (BRAF/MEKi) is frequently used for their clinical management. One major drawback of BRAF/MEKi targeted therapy is the rapid development of therapeutic resistance, which can occur via multiple mechanisms, including the metabolic rewiring of cancer cells that often involves the upregulation of mitochondrial bionergetics and NAD+ biosynthetic pathways. mTORC2 is a signaling complex that requires the presence of its essential RICTOR subunit to play its regulatory functions in cell growth and metabolism. mTORC2 is believed to play mostly pro-oncogenic roles in several tumor types, including melanoma. However, bioinformatics analysis of TCGA melanoma patients’ database revealed that low RICTOR levels in tumors correlate with an overall worse clinical outcome. GSEA analysis of low-RICTOR tumors evidenced also a gene expression signature suggestive of activation of mitochondrial energy producing pathways. On these bases, we have hypothesized that inhibition of mTORC2 activity may render BRAFV600E melanoma cells resistant to BRAFi/MEKi. We show here that RICTOR/mTORC2-deficient cells are intrinsically tolerant to BRAFi/MEKi, and anticipate the onset of resistance to BRAFi after sustained drug exposure both in vitro and in vivo, indicating that mTORC2 activity normally opposes the acquisition of targeted therapy resistance in BRAFV600E melanomas. Mechanistically, RICTOR-deficient cells show an enhanced mitochondrial respiratory potential and increased expression of nicotinamide phosphoribosyltransferase (NAMPT) protein, the rate-limiting enzyme of NAD+ salvage pathway, and pharmacological inhibition of these processes in RICTOR-deficient cells is sufficient to restore sensitivity to BRAFi. Thus, our work identifies a novel role for mTORC2 in favoring the responses of BRAF-mutated melanoma cells to targeted therapy, and suggest that the evaluation of the intratumor level of RICTOR may help to predict the responses of melanoma patients to these treatments.
HostingRepository	PRIDE
AnnounceDate	2024-05-23
AnnouncementXML	Submission_2024-05-23_00:54:07.048.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Enxhi Shaba
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	ultraflex

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-13 02:31:34	ID requested
⏵ 1	2024-05-23 00:54:07	announced

10.1186/s12943-024-02010-1;

Ponzone L, Audrito V, Landi C, Moiso E, Levra Levron C, Ferrua S, Savino A, Vitale N, Gasparrini M, Avalle L, Vantaggiato L, Shaba E, Tassone B, Saoncella S, Orso F, Viavattene D, Marina E, Fiorilla I, Burrone G, Abili Y, Altruda F, Bini L, Deaglio S, Defilippi P, Menga A, Poli V, Porporato PE, Provero P, Raffaelli N, Riganti C, Taverna D, Cavallo F, Calautti E, melanoma cells promotes resistance to BRAF/MEK inhibition. Mol Cancer, 23(1):105(2024) [pubmed]

submitter keyword: BRAFV600E, mTORC2, BRAF,Rictor, melanoma

Prof. Luca Bini
contact affiliation	Functional Proteomic Lab, Department of Life Sciences, University of Siena, Siena, Italy
contact email	luca.bini@unisi.it
lab head
Enxhi Shaba
contact affiliation	University of Siena
contact email	shaba3@student.unisi.it
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD045346

PRIDE project URI

• PRIDE
  1. PXD045346
     1. Label: PRIDE project
     2. Name: Rictor/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition