# Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $372,817

## Abstract

Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids
 Elevated cell surface levels of the human epidermal growth factor receptor subunit 3 (HER3) is associated
with resistance to a number of signal-blocking breast cancer treatments, including inhibitors of EGF-R (lapatinib),
HER2 (lapatinib, trastuzumab, T-DM1), HER2-3 (pertuzumab), and combination therapy. Additionally, HER3
elevation has been identified on “untarget-able” tumors such as triple-negative breast cancer (TNBC). Patients
with such refractory tumors currently have limited treatment options and a poor prognosis. Moreover, as up to
70% of cases resist or acquire resistance to signal-blocking therapies, an alternative approach addressing this
important clinical problem has the potential for significant clinical impact. We have developed a self-assembling
nanobiological particle, HerDox, which uses HER3 as a portal for targeted entry of toxic molecules. In contrast
to receptor-targeted antibodies and tyrosine kinase inhibitors currently used in the clinic, HerDox circumvents
the need to modulate signaling and can induce rapid entry of toxic molecules into tumor cells by receptor-
mediated endocytosis and membrane penetration. We have previously shown that HerDox can elicit targeted
toxicity to trastuzumab-resistant HER2+ tumors due to the augmented levels of HER3 on these cells in
association with resistance, while sparing heart and liver tissue. Whereas the prevalence of HER2-3
heterodimers on the HER2+ tumor cell surface can enable targeting by HerDox, naïve HER2+ tumors exposed
to trastuzumab undergo acute shift to a HER3+ phenotype and acquire augmented sensitization to HerDox
targeting and potency. EGFR inhibitors also have the same effect on both HER2+ and triple-negative breast
tumors in experimental models. These findings suggest that neoadjuvant treatment of primary tumors with clinical
inhibitors of HER2 or EGF-R can impart selective pressure on a heterogeneous tumor, driving expression of
surviving cells to a HER3 augmented phenotype and thus cornering these resistant tumors for HerDox attack.
This study will test this phenomenon in preclinical models of HER2+ and triple-negative tumors undergoing
treatment with targeted therapies currently used in the clinic or in clinical trials that are aimed at HER2 and EGF-
R, respectively. Our recent studies also show that HER3 is expressed on the blood-brain barrier (BBB) and can
facilitate passage of systemic HerDox across the BBB and into brain-localized HER3+ TNBC tumors. The brain
is a predominant site of metastasis for both TNBC and resistant HER2+ breast tumors, but most targeted
therapies that are effective extracranially lack significant impact on intracranial tumors and thus brain metastases
remain a significant clinical problem. Both HER2+ and TNBC tumors that escape intervention and metastasize
to the brain express high levels of HER3. Therefore, we will also evaluate the therapeutic efficacy of HerDox on...

## Key facts

- **NIH application ID:** 10367490
- **Project number:** 1R01CA258204-01A1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** LALI K MEDINA-KAUWE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,817
- **Award type:** 1
- **Project period:** 2022-05-09 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367490

## Citation

> US National Institutes of Health, RePORTER application 10367490, Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids (1R01CA258204-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10367490. Licensed CC0.

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