Dissertation
Investigation of novel therapeutic targets in RAC1-mutant melanoma
Doctor of Philosophy (Ph.D.), Drexel University
May 2023
DOI:
https://doi.org/10.17918/00001622
Abstract
Recent exome studies of cutaneous melanoma have identified RAC1P29S as 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 becoming 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 led to the identification of a unique sensitivity to pharmacologic inhibition or genetic knockout of CDK9 in RAC1P29S-expressing melanocytes and melanoma cells. Additionally, CDK9 inhibition primed melanoma cells for immunotherapy by increased surface expression of PD-L1 and MHC Class I in cells expressing the RAC1P29S mutation. Furthermore, combination of CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth in vivo 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.
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Details
- Title
- Investigation of novel therapeutic targets in RAC1-mutant melanoma
- Creators
- Alexa Christine Cannon
- Contributors
- Jonathan Chernoff (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vi, 100 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991020668710904721