# Targeting ERK5 for Colorectal Cancer Therapy

> **NIH NIH R21** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $273,488

## Abstract

ABSTRACT
Colorectal cancer (CRC) is diagnosed in about 140,000 patients in the US, with a mortality of 50,000 patients
per year. Almost half of these patients have either a RAS or BRAF mutation for which there is currently no
effective therapy. Activated MAPK signaling plays a major role in the pathogenesis of CRC. Pharmacological
inhibitors of mutant BRAFV600E, MEK1/2, and more recently ERK1/2 have been developed for targeted therapy.
Vertical targeting the MAPK pathway, particularly in combination with epidermal growth factor receptor (EGFR)
inhibitors to prevent its feedback activation, holds promise for the systemic treatment of CRC. However, primary
resistance to targeted therapy is a major obstacle in CRC, as compared with other cancers such as melanoma
and lung cancer which exhibit acquired resistance to therapy. Combinations of EGFR/RAF or RAF/MEK
inhibitors have been tested in the lab and clinic, and recently a triple inhibitor cocktail (EGFR/RAF/MEK) has
been clinically evaluated in BRAFV600E mutant CRC. However, in all studies residual MAPK signaling was
identified as a cause of resistance with low patient response rates. The mechanism of the residual MAPK
signaling is poorly understood. We have found a novel resistance mechanism in intestinal epithelial cells upon
genetic deletion of ERK1/2 in mice in vivo, as well as in response to treatment of human CRC cells with MEK
inhibitors in vitro. This molecular mechanism involves activation of an atypical MAPK family member, ERK5,
which provides a by-pass signaling pathway to the canonical MAPK signaling pathway. Thus, the hypothesis
upon which the studies are based is that “therapeutic targeting of ERK5, particularly when either RAS or BRAF
is the cancer driver, in combination with other targeted agents and/or chemotherapeutics will enhance inhibition
of CRC proliferation and metastasis. Pharmacological targeting of ERK5 in combination with EGFR, RAF and/or
MEK inhibitors will be particularly effective in CRC patients with oncogenic KRAS or BRAF mutations, as this
approach prevents acquired resistance via parallel pathways”. The studies we will conduct are to: investigate
the molecular mechanisms causing ERK5 upregulation in CRC and the role of ERK5 as a transcriptional activator
of angiogenesis in CRC cells; evaluate of ERK5 signaling in patient-derived CRC samples with KRAS mutations;
and an investigation of treatment of MEK inhibitor-resistant CRC patient derived xenografts with ERK5 targeted
agents. This an exploratory developmental research project to obtain preclinical data validating a potential new
clinical target, ERK5, responsible for tumor progression, angiogenesis and metastasis of CRC. The information
obtained will provide the basis for a clinical trial of the combination of an ERK5 inhibitor, with an EGFR/RAF/
MEK inhibitor cocktail in CRC patients.

## Key facts

- **NIH application ID:** 10021322
- **Project number:** 1R21CA244691-01A1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** GARTH POWIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $273,488
- **Award type:** 1
- **Project period:** 2020-05-13 → 2021-01-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021322

## Citation

> US National Institutes of Health, RePORTER application 10021322, Targeting ERK5 for Colorectal Cancer Therapy (1R21CA244691-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10021322. Licensed CC0.

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