PXD046960-1

PXD046960 is an original dataset announced via ProteomeXchange.

Title	Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints
Description	RAC1P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets for RAC1P29S-harboring melanomas. To investigate the RAC1P29S-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1P29S-mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1P29S-mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.
HostingRepository	PRIDE
AnnounceDate	2025-03-18
AnnouncementXML	Submission_2025-03-18_12:45:38.106.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Chernoff
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-14 14:47:10	ID requested
⏵ 1	2025-03-18 12:45:38	announced

10.1038/s41388-024-02947-z;

Cannon AC, Budagyan K, Uribe-Alvarez C, Kurimchak AM, Araiza-Olivera D, Cai KQ, Peri S, Zhou Y, Duncan JS, Chernoff J, Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints. Oncogene, 43(10):729-743(2024) [pubmed]

submitter keyword: PD-1,RAC1, melanoma, CDK9

Jonathan Chernoff
contact affiliation	Cancer Signaling and Microenvironment Program,Fox Chase Cancer Center, Philadelphia, PA, USA
contact email	J_Chernoff@fccc.edu
lab head
Jonathan Chernoff
contact affiliation	Fox Chase Cancer Center
contact email	J_Chernoff@fccc.edu
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/2025/03/PXD046960

PRIDE project URI

• PRIDE
  1. PXD046960
     1. Label: PRIDE project
     2. Name: Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints