# FOXD3 up-regulation and ERBB3 signaling as an adaptive response to BRAF inhibitors in melanoma

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2022 · $363,090

## Abstract

Project Summary
Melanoma is the deadliest form of skin cancer. We aim to understand mechanisms underlying
oncogenic signaling and drug resistance in melanoma in order to improve the current treatment
options. The serine/threonine kinase, BRAF, is somatically mutated in ~50% of melanomas and
drives hyper-activation of MEK-ERK1/2 signaling, aberrant growth and invasion. While BRAF and
MEK inhibitors are now first-line therapy for advanced-stage mutant V600E BRAF melanomas,
they only delay mortality. Thus, we must understand how to build on BRAF+MEK inhibitor
treatments and determine how to combine them with immune checkpoint agents, which remove the
blocks on T cell action. In the previous cycle of this grant, we showed that up-regulation of FOXD3-
ErbB3 signaling is an adaptive response to BRAF inhibitors that promotes a state of drug tolerance
in mutant BRAF melanoma. Furthermore, we showed that inhibition of ErbB3 enhanced the effects
of BRAF inhibitors in mutant BRAF melanomas in vivo. In this current proposal, we aim to identify
mechanisms regulating FOXD3 in mutant BRAF melanomas, test the possibility that epigenetic
BET/BRD inhibitors will block adaptive responses to BRAF+MEK inhibitors and alter the tumor
microenvironment, and determine how FOXD3 expression alters the infiltration/activation status of
tumor-associated immune cell populations and the expression of putative immune checkpoint
proteins. At the completion of our experiments, we expect to have identified tumor and stromal
markers for adaptive responses to targeted therapy and informed future combinatorial targeted
inhibitor, epigenetic inhibitor and immune-based therapeutic strategies in mutant BRAF melanoma.

## Key facts

- **NIH application ID:** 10451609
- **Project number:** 5R01CA160495-10
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Andrew Eric Aplin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,090
- **Award type:** 5
- **Project period:** 2012-06-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451609

## Citation

> US National Institutes of Health, RePORTER application 10451609, FOXD3 up-regulation and ERBB3 signaling as an adaptive response to BRAF inhibitors in melanoma (5R01CA160495-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451609. Licensed CC0.

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