Dana-Farber Preclinical Research Finds Opportunities for Treatment Improvements for HER2-positive Breast Cancer

Study Title: HER2 heterogeneous breast cancer models reveal novel therapeutic targets and subclonal dynamics during evolution to resistance to HER2-targeted therapies

Publication: Cancer Discovery

Dana-Farber Cancer Institute corresponding author: Kornelia Polyak, MD, PhD

Summary: Drugs that target human epidermal growth factor receptor 2 (HER2) have revolutionized the treatment of HER2-positive breast cancer. Many tumors, however, are heterogeneous, with a mix of high- and low-HER2 expression levels that is associated with worse responses and shorter survival after treatment with HER2-targeted medicines. Dana-Farber’s Kornelia Polyak, MD, PhD and Marie-Anne Goyette, PhD postdoctoral fellow in the lab developed models of HER2 heterogeneous breast cancer to study resistance to HER2-targeting antibody-drug conjugates such as T-DXd. 

Using these models, the team found that HER2-low cells were not as susceptible to killing by T-DXd than HER2-high cells. However, HER2-low cells promote regrowth of surviving HER2-high cells and the recurrence of HER2 heterogeneous tumors. CRISPR screens identified a factor called USP9X, the loss of which could sensitize HER2-low cells to T-DXd treatment. Data from a previous clinical trial strengthened the hypothesis, showing that higher USP9X expression was present in tumors after treatment with T-DM1 (another HER2-targeting  antibody-drug conjugate) in patients with HER2 heterogeneous tumors. In tests in their animal models, USP9X inhibitor in combination with T-DXd led to improved tumor suppression and longer recurrence-free survival. USP9X inhibitors are in the early stages of clinical development.

Significance: About 20 percent of breast cancer cases are HER2-positive. Tumors that contain a mix of HER2-high and HER2-low cells resist treatment with HER2-targeted medicines. This study uses novel preclinical models of HER2 heterogeneous breast cancer to uncover the mechanisms that drive treatment resistance. The findings support the consideration of HER2 heterogeneity in clinical decision making and suggest further study of a novel treatment strategy for overcoming resistance.

Funding: The National Institutes of Health, The Canadian Institutes of Health, the Cancer Research Society, and BMO Financial Group.