PXD028297

PXD028297 is an original dataset announced via ProteomeXchange.

Title	BRAF activation by metabolic stress promotes glycolysis and survival, sensitizing NRASQ61 mutated melanomas to targeted therapy.
Description	NRAS-mutated melanoma lacks an approved first-line treatment. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknow how the NRAS oncogene contributes to this cancer hallmark. Here, we show that NRASQ61-mutated melanomas harbor specific metabolic alterations that render cells sensitive to sorafenib upon metabolic stress. Mechanistically, these cells seem to depend on glucose metabolism, as glucose deprivation promotes the switch of the RAF isoform used from CRAF to BRAF. This process contributes to cell survival and sustains glucose metabolism through the phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/6- phosphofructo-2-kinase/fructose-2,6-bisphosph 3 (PFKFB2/PFKFB3) heterodimers by BRAF. In turn, this phosphorylation favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop linking glycolysis and the RAS signaling pathway. In vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with the combination of 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence of the contributions of NRAS oncogenes to metabolic rewiring and proof of principle for the treatment of NRAS-mutated melanoma with combinations of metabolic stress (glycolysis inhibitors) and already approved drugs such as sorafenib.
HostingRepository	PRIDE
AnnounceDate	2023-01-09
AnnouncementXML	Submission_2023-01-09_07:45:19.088.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	FrancescCanals
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2021-09-09 08:19:34	ID requested
⏵ 1	2023-01-09 07:45:23	announced

McGrail K, Granado-Mart, í, nez P, Esteve-Puig R, Garc, í, a-Ortega S, Ding Y, S, á, nchez-Redondo S, Ferrer B, Hernandez-Losa J, Canals F, Manzano A, Navarro-Sabat, é A, Bartrons R, Yanes O, P, é, rez-Alea M, Mu, ñ, oz-Couselo E, Garcia-Patos V, Recio JA, -mutated melanomas to targeted therapy. Nat Commun, 13(1):7113(2022) [pubmed]

submitter keyword: Melanoma

BRAF

NRAS mutation

Metabolic stress

PFKFB2

Juan ÁngelRecio
contact affiliation	Biomedical Research in Melanoma-Animal Models and Cancer Laboratory Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Hospital Barcelona-UAB Barcelona, 08035, Spain.
contact email	juan.recio@vhir.org
lab head
FrancescCanals
contact affiliation	Vall Hebron Institute of Oncology
contact email	fcanals@vhio.net
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/2023/01/PXD028297

PRIDE project URI

• PRIDE
  1. PXD028297
     1. Label: PRIDE project
     2. Name: BRAF activation by metabolic stress promotes glycolysis and survival, sensitizing NRASQ61 mutated melanomas to targeted therapy.