PXD050244

PXD050244 is an original dataset announced via ProteomeXchange.

Title	Nitrosylation-mediated regulation of MEK-ERK signaling in the NRAS-mutant melanoma
Description	NRAS activating mutations occur in 15-25% of melanoma patients. However, this subtype is more aggressive and refractory to current treatment modalities, including targeted MEK inhibitors, immunotherapies, and the recently emerging RAS inhibitors. Accordingly, identifying novel therapeutic targets and designing novel antimelanoma strategies is of utmost clinical relevance. Melanomas often harbor hyperactive nitric oxide synthases (NOS) which correlates strongly with poor prognosis. NOS is also known to be activated by ERK signaling. The nitric oxide so produced, induces nitrosylation, a post-translational modification, which dysregulates various kinases and phosphatases. We sensitized NRAS-mutant melanomas to targeted MEK inhibitors by inhibiting nitrosylation. This outcome revealed a strong correlation between global de-nitrosylation and downregulation of MEK-ERK cascade with a concomitant de-nitrosylation of NRAS and other small GTPases like Rho and Rac, dual specificity phosphatases, and ribosomal S6 kinase. In vivo, we observed extreme regression of NRAS-mutant melanoma tumors generated in an immunocompetent mouse model in response to a sequential nitrosylation inhibition and MEK inhibition. In addition to MEK-ERK downregulation, this strategy activated the CD8+ T cells in the tumor microenvironment. We conclude that while nitrosylation hyperactivates the RAS-RAF-MEK-ERK cascade, it also suppresses anti-melanoma immune response, bolstering progression and MEKi resistance. The underlying mechanism(s) will be crucial in identifying novel therapeutic vulnerabilities against aggressive, currently incurable NRAS-mutant melanomas with potential clinical application in other melanoma subtypes.
HostingRepository	PRIDE
AnnounceDate	2025-05-02
AnnouncementXML	Submission_2025-05-02_06:53:03.863.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD050244
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	biotinylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-29 10:40:44	ID requested
⏵ 1	2025-05-02 06:53:04	announced

10.6019/PXD050244;

10.1158/0008-5472.can-24-0693;

Srivastava J, Yadav VK, Jimenez RV, Phadatare PR, Inamdar NA, Young MM, Bacchiocchi A, Halaban R, Fang B, Pulido AM, Tsai KY, Smalley KSM, Koomen JM, Rodriguez PC, Premi S, Blocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors. Cancer Res, ():(2025) [pubmed]

submitter keyword: Nitrosylation, Signaling, Cancer,Melanoma, MAP Kinase

Sanjay Premi, PhD
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	sanjay.premi@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050244
     1. Label: PRIDE project
     2. Name: Nitrosylation-mediated regulation of MEK-ERK signaling in the NRAS-mutant melanoma