# Exploiting the distinct genomics and signaling of colorectal cancers to effectively target ERK

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $505,021

## Abstract

Genomic and biochemical studies indicate the central role of ERK signaling as the key driver of
colorectal cancer (CRC) proliferation. Yet selective RAF/MEK/ERK pathway inhibitors have
been ineffective in the treatment of CRC thus far. We hypothesize that profound ERK inhibition
is required to suppress the growth of ERK activated tumors and that high basal receptor-driven
RAS activation in CRC causes rapid adaptive and acquired resistance to ERK inhibition that is
not overcome with current inhibitors due to their narrow therapeutic index. Additionally,
augmenting this high basal receptor-driven RAS activation could provide sufficient ERK
activation to stimulate tumor growth, providing a selective pressure for genomic alterations that
amplify upstream signaling in CRC. In this proposal, we will define the spectrum of genomic
alterations in CRC that amplify ERK signaling and could be targeted with ERK inhibition and will
functionally and biochemically characterize novel alterations in the RAF and MEK proteins. We
will devise strategies that profoundly inhibit ERK by co-targeting ERK activation and receptor re-
activation and by using novel combinations and dosing schedules that expand the therapeutic
index of ERK inhibition. We have shown that high receptor tyrosine kinase (RTK) signaling in
CRC has consequences for response to targeted therapies as (1) response rates to RAF plus
RTK (i.e., EGFR) inhibitors is better than for RAF inhibitors alone in patients with BRAF V600E
CRC, (2) wild-type RAS amplification, a recurrent mechanism of resistance to RAF inhibitor
combinations in CRC never detected in the large number of analyzed RAF inhibitor-resistant
melanomas, increases activated RAS in an RTK-dependent manner, and (3) low activity BRAF
mutants in CRC can act as oncogenes by increasing signal transduction from activated RAS
and amplifying EGFR signaling. This proposal will now apply an understanding of these specific
lineage properties to define the molecular profiles that depend on ERK signaling and devise
effective strategies to inhibit ERK signaling in CRC in the clinic. We believe these studies will
guide the development of new treatments for CRC and improve the outcomes of patients with
these tumors.

## Key facts

- **NIH application ID:** 9834845
- **Project number:** 5R01CA233736-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Rona Yaeger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,021
- **Award type:** 5
- **Project period:** 2018-12-10 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834845

## Citation

> US National Institutes of Health, RePORTER application 9834845, Exploiting the distinct genomics and signaling of colorectal cancers to effectively target ERK (5R01CA233736-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9834845. Licensed CC0.

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