# Role of Erbb3 kinase activity in colorectal tumorigenesis.

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $434,298

## Abstract

The overarching goals of this proposal are to determine if Erbb3 kinase plays a critical role in colorectal
tumorigenesis and to test if colorectal cancer with oncogenic Erbb3 mutations respond better to anti-PD1
antibody. Erbb3, a member of the EGFR family of receptor protein tyrosine kinases, is mutated in a variety of
human cancers including colorectal cancer (CRC). Unlike other EGFR family members, the kinase domain of
Erbb3 is thought to be a pseudo-kinase without enzymatic activity. Although it is well documented that Erbb3
plays an oncogenic role in tumorigenesis, the mechanisms by which Erbb3 activation drives tumorigenesis are
largely unknown. We made the paradigm-shifting discovery that the pseudo-kinase domain of Erbb3 is a
serine/threonine (S/T) kinase activated by phosphorylation of a serine site in the juxatomembrane domain, and
that its kinase activity is required for robust tumor growth in both xenograft and genetically engineered mouse
models. Moreover, we found that a Erbb3 kinase-dead mutant impairs interferon-γ (IFN-γ)-induced PD-L1
expression in CRCs. Interestingly, knockin of an oncogenic Erbb3 mutation in mouse colon cancer cell lines
renders them sensitive to anti-PD1 antibody therapy. Here we propose two aims to determine the role of Erbb3
S/T kinase in (1) colorectal tumorigenesis and (2) the response of colorectal cancers to immune checkpoint
inhibitors. Successful completion of our proposed studies will lay a solid foundation for targeting Erbb3 mutant
CRCs with Erbb3 kinase inhibitors and/or immune checkpoint inhibitors. Given that aberrant activation of Erbb3
causes resistance to various cancer therapies including Herceptin in breast cancer and EGFR inhibitors in lung
cancer, the impact of our studies will have a broad impact on cancer therapy.

## Key facts

- **NIH application ID:** 10114359
- **Project number:** 1R01CA256791-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Zhenghe Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,298
- **Award type:** 1
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114359

## Citation

> US National Institutes of Health, RePORTER application 10114359, Role of Erbb3 kinase activity in colorectal tumorigenesis. (1R01CA256791-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10114359. Licensed CC0.

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