# Redefining indications of EGFR inhibitors in cancers that harbor mutant RAS

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $356,850

## Abstract

Background: Anti-EGFR agents have been shown to benefit colorectal cancer patients, except for patients
whose tumor includes a KRAS mutation. Data from multiple clinical trials suggest this may be incorrect.
Colorectal cancer patients with KRAS G13D appear to benefit from anti-EGFR agents. Controversy surrounds
this observation because it contradicts the well-established mechanisms of EGFR signaling and Ras mutations.
We have investigated the problem with a novel experimental-systems approach of Ras signaling, revealing a
non-intuitive dependency on EGFR that follows from differences in how KRAS mutants interact with tumor
suppressor neurofibromin (NF1) to influence wild-type RAS activation thereby.
Moreover, we have identified an additional 10 mutants that so not bind NF1 and confer sensitivity to EGFR
inhibition. Here we propose to study the remaining mutants that makeup over 90% of the RAS mutations in
CRC. Furthermore, we have devised a strategy to selectively target WT RAS in the resistant RAS alleles to
sensitize CRC to EGFR inhibitors.
Overarching Hypothesis:
We plan to characterize these mutants with hypothesis driven independent aims:
Aim 1 Functional mechanistic studies will test RAS candidates determined by their ability to bind NF1 for EGFR
inhibitor sensitivity.
Aim 2 Pharmacologically target WT-RAS in CRC cells that harbor mutant KRAS alleles that confer intrinsic
resistance to EGFR inhibitors.
Aim 3 Leverage dominant/negative effects of cytosolic NRAS mutants with EGFR inhibition.
Long term goal: It is increasingly believed that combining experimental and computational methods will be
required to match patients with treatments. Our work demonstrates how systems approaches enable
mechanism-based inference concerning how mutations influence the response to treatment. Our current findings
suggest that we can identify more candidates and sensitize resistant alleles by targeting WT-RAS processing.
This potentially could increase the number of patients with EGFR inhibitors that currently cannot receive this
therapy.

## Key facts

- **NIH application ID:** 10799827
- **Project number:** 1R01CA276771-01A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Thomas Bradley McFall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $356,850
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799827

## Citation

> US National Institutes of Health, RePORTER application 10799827, Redefining indications of EGFR inhibitors in cancers that harbor mutant RAS (1R01CA276771-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10799827. Licensed CC0.

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