# Targeting ERK5 for Colorectal Cancer Therapy

> **NIH NIH R21** · PHUSIS THERAPEUTICS, INC. · 2021 · $169,469

## 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
or acquired resistance to targeted therapy is a major obstacle, particularly in CRC as compared with other
cancers such as melanoma and lung cancer. 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 the studies reactivation of MAPK signaling was identified as a cause
of resistance and low patient response rates. The mechanism of the reactivation of 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
mechanism causing ERK5 upregulation 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, invasion 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:** 10357462
- **Project number:** 7R21CA244691-02
- **Recipient organization:** PHUSIS THERAPEUTICS, INC.
- **Principal Investigator:** GARTH POWIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,469
- **Award type:** 7
- **Project period:** 2020-05-13 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357462

## Citation

> US National Institutes of Health, RePORTER application 10357462, Targeting ERK5 for Colorectal Cancer Therapy (7R21CA244691-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10357462. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*