PXD050614

PXD050614 is an original dataset announced via ProteomeXchange.

Title	RICTOR/mTORC2 downregulation in BRAF V600E melanoma cells promotes resistance to BRAF/MEK inhibition
Description	Background 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 define in this context the specific role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit and regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing the TCGA 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 in vitro. We performed a 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 We found that low RICTOR levels in MM correlate with an overall worse clinical outcome. GSEA of low- RICTOR tumors revealed a gene expression signature suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy producing pathway. RICTOR-deficient BRAF V600E cells are intrinsically tolerant to BRAFi/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. In RICTOR- depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, while their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils a novel tumor suppressing role for mTORC2 in the responses 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 support the concept that the evaluation of intra-tumor RICTOR levels in MM has a prognostic value, and may help predicting the response of patients to targeted therapy.
HostingRepository	PRIDE
AnnounceDate	2024-06-22
AnnouncementXML	Submission_2024-06-22_08:29:30.121.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lorenza Vantaggiato
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	ultraflex

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-14 07:07:29	ID requested
⏵ 1	2024-06-22 08:29:31	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: Targeted therapy, RICTOR, BRAF V600E melanoma, Mitochondrial metabolism, Drug resistance, NAMPT,mTORC2

Lorenza Vantaggiato
contact affiliation	University of Siena
contact email	lorenz.vantaggiato2@unisi.it
lab head
Lorenza Vantaggiato
contact affiliation	University of Siena
contact email	lorenz.vantaggiato2@unisi.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050614
     1. Label: PRIDE project
     2. Name: RICTOR/mTORC2 downregulation in BRAF V600E melanoma cells promotes resistance to BRAF/MEK inhibition