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Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics during Evolution to
Marie-Anne Goyette1,2,3, Christopher Graser4,5,6, Marco Seehawer1,2,3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Intratumor heterogeneity for human epidermal growth factor receptor 2 (HER2) in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous (HET) tumors has been hindered by the lack of preclinical models that accurately mimic the human disease. In this study, we describe human HER2 HET breast cancer models composed of ERBB2-amplified (HER2hi) and nonamplified (HER2lo) cell populations derived from the same tumor. Utilizing these models, together with cellular barcoding, we demonstrate subclonal cooperation between HER2hi and HER2lo subpopulations. Furthermore, HER2lo cells drive resistance to HER2-targeting antibody-drug conjugates (ADC) like trastuzumab deruxtecan (T-DXd) but are sensitive to HER2 kinase inhibitors. CRISPR screens in HET cocultures identified sensitizers of HER2lo cells to T-DXd, including ATP-binding cassette subfamily C member 1 and ubiquitin-specific peptidase 9 X (USP9X). USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.
Significance:
Studies of HER2 HET breast cancer models demonstrated that HER2lo cells drive HER2-targeting ADC resistance and accelerate recurrence by cooperating with HER2hi cells. We identified novel therapeutic strategies to sensitize HER2lo cells to T-DXd, providing mechanistic insight and offering promising avenues to overcome resistance and improve patient outcomes.
Insights
Intratumor HER2 heterogeneity in breast cancer drives treatment resistance. New models reveal HER2-low cells resist antibody-drug conjugates but new drug targets like USP9X can overcome this resistance.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Intratumor heterogeneity of HER2 (human epidermal growth factor receptor 2) in HER2-positive breast cancer contributes to therapeutic resistance.
- Existing preclinical models do not fully replicate human HER2 heterogeneity, limiting treatment development.
Purpose of the Study:
- To develop and characterize human HER2 heterogeneous breast cancer models.
- To investigate subclonal cooperation and resistance mechanisms in HER2 heterogeneous tumors.
- To identify novel therapeutic strategies to overcome resistance to HER2-targeted therapies.
Main Methods:
- Generation of HER2 heterogeneous breast cancer models from ERBB2 amplified (HER2hi) and non-amplified (HER2lo) cell populations.
- Cellular barcoding to track subclonal dynamics.
- CRISPR screens to identify sensitizers for HER2-low cells.
- Assessment of drug sensitivity to HER2-targeting agents and kinase inhibitors.
Main Results:
- HER2 heterogeneous models demonstrated subclonal cooperation between HER2hi and HER2lo subpopulations.
- HER2lo cells conferred resistance to HER2-targeting antibody-drug conjugates (ADCs) like T-DXd but remained sensitive to HER2 kinase inhibitors.
- CRISPR screens identified ABCC1 and USP9X as sensitizers for HER2lo cells to T-DXd.
- USP9X inhibition improved HER2 lysosomal targeting, enhanced ADC payload release, and reduced tumor recurrence.
Conclusions:
- HER2 heterogeneity plays a critical role in treatment resistance in HER2-positive breast cancer.
- Targeting USP9X can overcome resistance to ADCs in HER2 heterogeneous tumors by enhancing drug efficacy.
- These findings support the development of improved therapeutic strategies for HER2 heterogeneous breast cancers.
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