# Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2022 · $231,831

## Abstract

Project summary / abstract
Breast cancers overexpressing both the HER2 oncogene and hormone receptors (HR) are common among
young women, comprising up to 20% of all breast cancer cases and significantly contributing to mortality in this
patient population. These cancers represent a unique challenge because of a cross-talk between the HER2
and HR pathways, leading to targeted therapy resistance commonly mediated by activation of the cyclin D1 /
CDK4/6 complex downstream of HER2 and HR signalling cascades. At present, the vast majority of patients
with metastatic HR+/HER2+ breast cancer are treated with chemotherapy associated with multiple side effects,
because several standard of care targeted drug combinations failed to improve overall survival in phase III
clinical trials. Based on a strong signalling rationale and preliminary data obtained in our laboratory, I proposed a
triple combination of targeted agents - HER2 small molecule inhibitor tucatinib, aromatase inhibitor letrozole, and
CDK4/6 inhibitor palbociclib - as a novel targeted approach for treatment of HR+/HER2+ disease. After
demonstrating high activity of this combination in preclinical experiments, I opened an investigator-initiated
multicenter clinical trial of tucatinib, palbociclib and letrozole for patients with HR+/HER2+ metastatic breast
cancer. This trial was opened in November 2017 and has already shown a favourable safety and efficacy profile:
as
longest
of the October 1 st 2018 data cut off, with 18 out of 40 patients enrolled, clinical benefit rate was 75%, with the
duration of response of 8 months and ongoing.Triple combination targeted therapy has high potential to
challenge current standard of care front line chemotherapy approach for patients with HR+/HER2+ metastatic
disease. Therefore, it is critically important to develop a biomarker to allow stratification of patients into those
who will ultimately need chemotherapy, and those who will respond to front line triple targeted combination,
and may have long term disease control and improved quality of life with an oral targeted regimen. In this
application, I propose a comprehensive approach to identify pathways of intrinsic sensitivity and acquired
resistance to triple combination targeted therapy with the ultimate goal of developing a biomarker of response
to this therapy. I have already identified several potential drivers of acquired resistance via sequencing of drug
resistant tumor cell lines. These potential biomarkers will be validated in cell line based functional assays and
animal models. Additionally, patient tumor samples from the tucatinib, palbociclib and letrozole clinical trial will
be analyzed by total mRNA sequencing to identify the pathways and genes of intrinsic sensitivity to therapy,
and these pathways will be validated in vitro and in vivo. Moreover, using a liquid biopsy approach, I will
develop a predictive panel of biomarkers in circulating tumor cells, to allow a non-invasive monitoring of
bi...

## Key facts

- **NIH application ID:** 10460233
- **Project number:** 5K08CA241071-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Elena Shagisultanova
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,831
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460233

## Citation

> US National Institutes of Health, RePORTER application 10460233, Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer (5K08CA241071-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10460233. Licensed CC0.

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