# Role of HER2 mutations in breast cancer progression and response to targeted therapies

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $368,327

## Abstract

ABSTRACT
Activating mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase (RTK), occur in ~3% of
human tumors and correlate with poor prognosis in breast cancer. Since HER2 mutations usually occur in the
absence of HER2 gene amplification, there are currently no approved therapies for this breast cancer subtype.
A subset of patients with HER2-mutant breast cancers exhibit excellent clinical responses to anti-HER2
therapies such as the tyrosine kinase inhibitor (TKI) neratinib, suggesting that HER2 mutations are oncogenic
drivers. However, the molecular mechanisms by which mutant HER2 promotes breast cancer progression are
poorly understood and the response of the most common HER2 mutants to the multiple available anti-HER2
therapies has not been systematically investigated. Finally, durable clinical responses to HER2 TKIs are not
the rule and are generally transient, suggesting mechanisms of drug resistance that remain to be discovered.
Our objectives are to determine the mechanisms by which mutant HER2 promotes breast cancer oncogenesis
and to identify the treatments that are most effective against HER2-mutant breast cancers. We hypothesize
that 1) recurrent HER2 mutations generate gain-of-function activity and, as such, tumor dependence on
aberrant HER2 signaling, which can be inhibited with targeted therapies; 2) HER2 mutations cooperate with
co-occurring mutations in other ERBB RTKs to promote breast cancer growth; and 3) co-occurring genomic
alterations will lead to intrinsic or acquired resistance to HER2 TKIs in HER2-mutant cancers.
To test these hypotheses, we propose the following three aims: 1) To define mechanisms by which HER2
mutants promote breast oncogenesis and cancer progression; 2) To examine whether HER2 mutations
cooperate with alterations in other ERBB RTKs; and 3) To identify mechanisms of resistance to HER2 TKIs in
HER2-mutant breast cancers. We propose to integrate structural, biochemical, molecular and in vivo
approaches to complete these aims. We will use computational modeling and phospho-protein arrays to
determine the mechanisms by which HER2 mutations exert their tumorigenic properties, and will use inhibitors
of HER2 signaling to block these effects in HER2-mutant cell lines and patient-derived xenografts (PDXs). We
will model cooperation between observed co-occurring mutations in HER2/EGFR and HER2/HER3 in vitro and
in vivo. We will employ a genome-wide genetic screen to identify genes that promote resistance to neratinib ±
antiestrogens in HER2-mutant breast cancer cells. Finally, we will develop models of acquired resistance to
neratinib using HER2-mutant PDXs and identify mechanisms of resistance by next-generation DNA and RNA
sequencing, which will be confirmed in patient samples from the SUMMIT clinical trial. These studies will
determine the best drug combinations to use in order to inhibit mutant HER2-driven cancer progression and
will identify strategies to overcome resistance to HER2 muta...

## Key facts

- **NIH application ID:** 10214565
- **Project number:** 5R01CA224899-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carlos L Arteaga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,327
- **Award type:** 5
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214565

## Citation

> US National Institutes of Health, RePORTER application 10214565, Role of HER2 mutations in breast cancer progression and response to targeted therapies (5R01CA224899-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10214565. Licensed CC0.

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