# Therapeutic resistance and tumor heterogeneity in BRAF mutant colorectal cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $396,501

## Abstract

Project Summary
 BRAF V600 mutations occur in ~10% of colorectal cancers (CRCs), leading to constitutive activation of
the MAPK signaling pathway, and confer a ~2-fold increase in mortality relative to BRAF wildtype CRC. Thus,
novel effective therapies for this disease are critically needed. While RAF inhibitors (RAFi), such as
vemurafenib and dabrafenib, are highly effective in BRAF mutant melanoma (~60-80% response rate), the
response rate to RAFi monotherapy in BRAF mutant CRC is only ~5%. Our initial efforts to define the
resistance mechanisms operant in BRAF mutant CRC have led to novel clinical trials of RAFi combinations.
Through this focused integration of laboratory models, clinical trials, and analysis of clinical specimens,
significant advances in the care of BRAF mutant CRC patients have been achieved, with response rates
increasing from ~5% to ~40% in the last few years. Still, a substantial percent of patients fail to respond to
therapy, and those patients that do respond eventually develop resistance. Accordingly, further optimization of
therapy is critically needed for BRAF mutant CRC. Therefore, we propose an innovative, highly translational
approach leveraging detailed signaling studies utilizing established and patient-derived tumor models,
comprehensive molecular assessment and characterization of patient-derived tumor models from tumor
biopsies from BRAFm CRC patients enrolled in cutting-edge clinical trials, and serial liquid biopsy analysis of
plasma ctDNA to define primary and acquired resistance mechanisms and the role of heterogeneity in BRAFm
CRC. We will also evaluate a novel convergent inhibition strategy employing ERK inhibitors, supported by our
preliminary data, as a potential strategy to overcome resistance. This proposed work will provide key insights
to guide development of novel and more effective therapeutic strategies for future clinical trials.

## Key facts

- **NIH application ID:** 9965796
- **Project number:** 5R01CA208437-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ryan Bruce Corcoran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,501
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965796

## Citation

> US National Institutes of Health, RePORTER application 9965796, Therapeutic resistance and tumor heterogeneity in BRAF mutant colorectal cancer (5R01CA208437-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9965796. Licensed CC0.

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