Unraveling Vulnerabilities in Endocrine Therapy-Resistant HER2+/ER+ Breast Cancer
Shaymaa Bahnassy1, Hillary Stires2, Lu Jin1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Endocrinology
|October 28, 2023
Summary
New models of endocrine therapy-resistant HER2+/ER+ breast cancer reveal vulnerabilities. Combining GPX4 inhibitors with anti-HER2 agents shows promise for treating this challenging breast cancer subtype.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- HER2-overexpressing breast cancer (BCa) with ER positivity (HER2+/ER+) shows intrinsic resistance to endocrine therapy (ET).
- Patients with HER2+/ER+ BCa respond less effectively to ET compared to HER2-/ER+ BCa.
- A significant number of HER2+/ER+ patients receive ET monotherapy, presenting a clinical challenge.
Purpose of the Study:
- To develop and characterize in vitro models of ET-resistant (ETR) HER2+/ER+ BCa.
- To identify potential therapeutic vulnerabilities in ETR HER2+/ER+ BCa.
- To understand the distinct phenotypes and molecular alterations in ET-resistant HER2+/ER+ BCa.
Main Methods:
- Development of two long-term estrogen deprivation (LTED) cell lines (BT474 and MDA-MB-361) to mimic AI resistance.
- Growth assays, PAM50 subtyping, genomic, transcriptomic, and single-cell RNA sequencing analyses.
- Functional studies involving GPX4 inhibitor and anti-HER2 agent combination therapy.
Main Results:
- MM361 LTEDs exhibited faster growth, ER loss, and increased HER2 expression; BT474 LTEDs showed slower growth with maintained ER and HER2 expression.
- Both LTED variants displayed reduced responsiveness to fulvestrant.
- MM361 LTEDs showed mutations in transcription factors/chromatin modifiers, a shift to non-luminal phenotypes, and upregulated lipid metabolism and ferroptosis-associated genes (e.g., GPX4).
- Combination therapy with a GPX4 inhibitor and anti-HER2 agents induced significant cell death in both models.
Conclusions:
- The developed BT474 and MM361 AI-resistant models represent distinct phenotypes of HER2+/ER+ BCa.
- Altered lipid metabolism and ferroptosis remodeling are identified as key vulnerabilities in ET-resistant HER2+/ER+ BCa.
- Targeting GPX4 in combination with anti-HER2 agents offers a potential therapeutic strategy for ETR HER2+/ER+ breast cancer.
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