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Journal article
Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints
Oncogene, v 43(10), pp 729-743
01 Mar 2024
PMID: 38243078
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
RAC1
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 RAC1
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 RAC1
-harboring melanomas. To investigate the RAC1
-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1
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 RAC1
-mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1
-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 RAC1
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.
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Details
- Title
- Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints
- Creators
- Alexa C Cannon - Drexel University College of Medicine, Philadelphia, PA, USAKonstantin Budagyan - Fox Chase Cancer CenterCristina Uribe-Alvarez - Fox Chase Cancer CenterAlison M Kurimchak - Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USADaniela Araiza-Olivera - Fox Chase Cancer CenterKathy Q Cai - Fox Chase Cancer CenterSuraj Peri - Fox Chase Cancer CenterYan Zhou - Fox Chase Cancer CenterJames S Duncan - Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USAJonathan Chernoff - Fox Chase Cancer Center
- Publication Details
- Oncogene, v 43(10), pp 729-743
- Grant note
- R01 CA211670 / NCI NIH HHS P30 CA006927 / NCI NIH HHS T32 CA009035 / NCI NIH HHS CA227184 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01 CA227184 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001146037800002
- Scopus ID
- 2-s2.0-85182708929
- Other Identifier
- 991021861284904721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Genetics & Heredity
- Oncology