# Understanding and Overcoming Resistance to BRAF/MEK Kinase Inhibitors in Melanoma

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $510,510

## Abstract

The vast majority (>80%) of patients with BRAFV600E/K melanomas initially respond to highly
specific BRAFV600E/K inhibitors as monotherapy or BRAF/MEK inhibitor combination therapy,
but at varying levels. Nearly all patients relapse after three months to two years, despite that all
of their tumor cells are carrying the BRAF mutations. In this application, we focus on the
biological dynamics of small populations within BRAFV600E/K melanomas that are a priori
resistant or rapidly adapt upon treatment and drive eventual relapse. In the first aim we will
follow the dynamics of mutant BRAFV600E/K melanoma cells treated with BRAF and MEK
inhibitor combinations. We have identified a slow-cycling subpopulation that is dynamically
changing as the cells survive the initial treatment, then persist and finally regrow with acquired
resistance to a variety of drugs. We will follow the cells in in vitro and in vivo models of human
melanoma using bar codes and single cell RNA analyses. These studies will not only determine
whether minor subpopulation(s) evolve under drug treatment stochastically or hierarchically, but
also will provide us with information on their pre-existence and/or whether malignant cell
plasticity is the major reason for intra-tumor heterogeneity to drug responses. In the second aim,
we are testing the hypothesis that intrinsically resistant subpopulations of cells present new
therapeutic opportunities that, if targeted, will specifically inhibit the onset of resistance. Our
preliminary studies using CRISPR/Cas9 have allowed us to functionally dissect the pathways
that form these rare subpopulations and, separately, the pathways that allow those
subpopulations to reprogram. We will validate hits in 3D culture systems and in in vivo mouse
models. We expect that targeting separate aspects of the resistance process in a rationally
designed way (in vitro and then in preclinical studies) will enable the reduction of resistance
onset upon BRAF/MEK inhibitor therapy.

## Key facts

- **NIH application ID:** 10070602
- **Project number:** 5R01CA238237-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Meenhard F Herlyn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $510,510
- **Award type:** 5
- **Project period:** 2019-12-13 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070602

## Citation

> US National Institutes of Health, RePORTER application 10070602, Understanding and Overcoming Resistance to BRAF/MEK Kinase Inhibitors in Melanoma (5R01CA238237-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10070602. Licensed CC0.

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