# Dissecting the evolution of targeted therapy resistance in BRAFV600E-mutant cancer

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $48,007

## Abstract

PROJECT SUMMARY
BRAFV600E mutation, the most common BRAF mutation, is found in approximately 3% of lung adenocarcinomas
and 50% of melanomas and presents a significant disease burden. While RAF inhibitors, alone or in combination
with MEK inhibitors, have improved survival, resistance eventually arises and patients progress on therapy. More
effective treatments are urgently needed, especially for patients with advanced disease. Our previous work
showed that propagation of resistance-causing alterations, such as BRAFV600E-amplification, is due to an
inadequate fitness threshold imposed by therapy, where fitness threshold refers to the barrier subclones must
overcome for continued growth. This suggests that a combination therapy consisting of multiple-drugs would be
more effective. We designed an intermittent RAF, MEK, and ERK inhibitor regimen that inhibited tumor growth
in a panel of lung adenocarcinoma and melanoma patient-derived xenograft (PDX) models, even those with
known resistance-causing alterations to single agents. The goal of this project is to assess the durability of
response to the intermittent three-drug combination, and to elucidate tumor clonal interactions that may facilitate
the evolution of resistance. Specifically, in Aim 1, I will a) evaluate the long-term treatment response to the
intermittent three-drug combination in PDX models; b) identify resistance mechanisms through deep targeted
sequencing; and c) evaluate the effect of treatment on tumor clonal architecture using novel single cell DNA
sequencing. In Aim 2, using BRAFV600E-amplification as a model and fluorescently barcoded single cell clonal
expansions as my experimental system, I plan to a) identify clonal interaction mechanisms that support the
growth of resistant clones and b) prospectively track the effect of therapy on tumor clonal composition. These
studies will improve understanding of the determinants of evolution of targeted therapy resistance and enable
the design of more effective treatments, as well as identify a therapeutic combination that may be curative for
some BRAFV600E-mutant cancers.
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## Key facts

- **NIH application ID:** 10218100
- **Project number:** 5F30CA232549-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jenny Yaohua Xue
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,007
- **Award type:** 5
- **Project period:** 2018-07-16 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218100

## Citation

> US National Institutes of Health, RePORTER application 10218100, Dissecting the evolution of targeted therapy resistance in BRAFV600E-mutant cancer (5F30CA232549-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218100. Licensed CC0.

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