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Author ORCID Identifier
Date Available
5-11-2026
Year of Publication
2024
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Pharmacology and Nutritional Sciences
Faculty
Dr. Rina Plattner
Faculty
Dr. Robert Hadley
Abstract
This study addresses the escalating incidence of NRAS-mutant melanomas, a type of skin cancer lacking FDA-approved targeted therapies. Despite ongoing research targeting the RAF/MEK/ERK pathway, existing drugs fail to enhance progression-free survival due to acquired resistance. This project identifies a novel role for ABL1/2 and DDR1 kinases in driving drug resistance and proliferation of NRAS-mutant melanoma cells. ABL1/2 and DDR1 cooperate to promote RAF homodimerization and protein stability in order to reactivate MEK/ERK signaling to drive MEK1/2 inhibitor (MEKi) resistance and promote survival of resistant cells. By targeting ABL1/2 and DDR1 with nilotinib, a FDA-approved anti-leukemic inhibitor, we reversed ERK1/2 reactivation and delayed proliferation of MEKi resistant cells both in vitro and in vivo. These findings suggest that ABL1/2 and DDR1 are potential therapeutic targets, and the combination of nilotinib with a MEK1/2 inhibitor may be a promising strategy for treating patients with refractory NRAS-driven melanomas.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.171
Funding Information
This study was supported by the following grants:
- the Lloyd Charitable Trust from 2018-2021,
- Markey Cancer Center Cancer Center Support Grant (CCSG) Pilot Award from 2018-2020,
- Markey Cancer Foundation Women's Strong Award from 2017-2020 and 2023-2025, and
- National Institute of Health/National Cancer Institute (no.: R01CA211137) from 2018-2024.
Recommended Citation
Lyon, Anastasia, "ABL1/2 AND DDR1 COOPERATE TO STABILIZE BRAF/CRAF TO DRIVE ERK1/2 REACTIVATION AND PROMOTE MEK INHIBITOR RESISTANCE IN NRAS-MUTANT MELANOMAS" (2024). Theses and Dissertations--Pharmacology and Nutritional Sciences. 55.
https://uknowledge.uky.edu/pharmacol_etds/55
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Biochemistry Commons, Bioinformatics Commons, Cancer Biology Commons, Cell Biology Commons, Molecular Biology Commons, Pharmacology Commons, Skin and Connective Tissue Diseases Commons
