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

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,189

## Abstract

PROJECT SUMMARY/ABSTRACT
Targeted immunotherapies against BRAFV600E/K-positive melanoma cancers have been
efficacious at eradicating disease in >80% of patients. Nevertheless, the existence of populations
of pre-resistant rare cells has posed a challenge to the efficacy of melanoma-targeted therapies,
often leading to a disease relapse in the majority of patients. In the parent R01 grant, we proposed
a multi-faceted approach combining new experimental techniques, statistical analysis, and theory
to understand the origin of these rare, transient drug-resistant cell states and devise strategies to
control them. In the current administrative supplement, our goal is to dissect the primordial cellular
pathways governing cellular reprogramming that convert the transient state of resistance in the
rare single cells into the permanent state of drug resistance that drive relapse. This work is related
to the parent R01, but explores new concepts and experimental designs. By using a low dose
exposure regimen, followed by high dose exposures, we seek to investigate whether a selective
or an adaptive cellular response underlies the mechanism resulting in the conversion to
permanent drug resistance. In a selection response, the permanently resistant cells share the
same final resistant properties as the transient initial population. In an adaptive response,
however, the final resistant properties of the permanently resistant cells could be different, most
likely greater, than that of the initial transient cells. We will employ a multi-pronged approach
consisting of single cell imaging, single cell barcoding, single cell RNA FISH, RNA sequencing
and computational biology techniques to elucidate the primordial cellular/molecular regulators
driving cellular reprogramming that results in permanently resistant cells. The mechanisms
revealed by these studies will be important for the development of new targeted therapies that
will be able to eradicate the relapse caused by therapy resistant cells.

## Key facts

- **NIH application ID:** 10381269
- **Project number:** 3R01CA238237-02S1
- **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:** $46,189
- **Award type:** 3
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381269

## Citation

> US National Institutes of Health, RePORTER application 10381269, Understanding and Overcoming Resistance to BRAF/MEK Kinase Inhibitors in Melanoma (3R01CA238237-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10381269. Licensed CC0.

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