Author ORCID Identifier

https://orcid.org/0000-0002-7365-4035

Date Available

5-11-2026

Year of Publication

2024

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

First Advisor

Dr. Rina Plattner

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.

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Available for download on Monday, May 11, 2026

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