# Targeting Abl kinases in BRAF-driven melanomas

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $348,484

## Abstract

Despite the success of new targeted agents and immunotherapies, metastatic melanoma remains an incurable
disease for many patients. Although BRAF inhibitors (BRAFi) show promise for reducing metastatic burden,
some melanomas are intrinsically resistant, and most responding patients eventually acquire resistance. These
data underline the importance of identifying new markers for treatment response and novel drug combinations
for treating metastatic and BRAFi-resistant disease. We show that Abl/Arg non-receptor tyrosine kinases are
highly expressed in melanoma, and are activated in a subset (40-60%). Moreover, SFKs and BRAFV600E, the
most common genetic alteration in melanoma, both contribute to Abl/Arg activation in melanoma cells. Once
activated, Abl/Arg promote proliferation, survival, a switch in EMT transcription factor expression, invasion, and
metastasis and bidirectionally regulate and potentiate BRAFV600E signaling. Moreover, inhibitors of Abl/Arg and
a parallel pathway, which drives intrinsic BRAFi resistance (PI3K/Akt/PTEN), cooperate to prevent melanoma
viability and tumor growth. Based on these findings, we hypothesize that BRAFV600E/ERK and SFKs
cooperatively activate Abl/Arg, which synergize with Akt to drive melanoma development, progression,
phenotypic switching and subsequent resistance. We propose a comprehensive hypothesis-driven
experimental design that will establish Abl/Arg as novel and exploitable drug targets. Aim 1 will define the
mechanism by which Abl/Arg are activated in melanoma. To achieve our objective, biochemical, molecular
biological and cell biological approaches using melanocytes, melanoma cell lines, tissue microarrays,
pharmacological inhibitors/RNAi, mass spectrometry, and immunohistochemistry will be used to test the
prediction that BRAFV600E/ERK-mediated phosphorylation prevents nuclear targeting of Abl and facilitates
activation of Abl/Arg by SFKs. In Aim 2, 2D/3D culture, rescue experiments and xenograft approaches will be
used to identify the mechanism by which Abl/Arg drive the EMT transcription factor switch, potentiate
BRAFV600E signaling, and promote acquired BRAFi resistance. Finally, in Aim 3, genetically engineered (GEM)
and xenograft mouse models as well as loss- and gain-of-function approaches will be used to test the
prediction that Abl/Arg cooperate with activated Akt, in mutant PTEN melanomas, to promote melanoma
growth/metastasis and BRAFi/MEKi resistance. Data obtained from this project not only will allow us to gain
important insight into fundamental mechanisms by which Abl/Arg are activated in melanoma, which likely is
applicable to other solid tumors, but also may lead to clinical studies testing the efficacy of Akt inhibitors in
combination with Abl/Arg inhibitors for treating mutant BRAF/PTEN melanomas, which often are resistant to
current therapeutic approaches.

## Key facts

- **NIH application ID:** 10221629
- **Project number:** 5R01CA211137-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** RINA PLATTNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,484
- **Award type:** 5
- **Project period:** 2018-08-13 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221629

## Citation

> US National Institutes of Health, RePORTER application 10221629, Targeting Abl kinases in BRAF-driven melanomas (5R01CA211137-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10221629. Licensed CC0.

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