Pre-Clinical Rationale for Amcenestrant Combinations in HER2+/ER+ Breast Cancer
Amira F Mahdi1,2, Niall Ashfield1, John Crown1,3
1Cancer Biotherapeutics Research Group, Life Sciences Institute, School of Biotechnology, Dublin City University, Dublin 9, D09 NR58 Dublin, Ireland.
Abstract:
HER2-positive/oestrogen receptor-positive (HER2+/ER+) represents a unique breast cancer subtype. The use of individual HER2- or ER-targeting agents can lead to the acquisition of therapeutic resistance due to compensatory receptor crosstalk. New drug combinations targeting HER2 and ER could improve outcomes for patients with HER2+/ER+ breast cancer. In this study, the pre-clinical rationale is explored for combining amcenestrant (Amc), a selective oestrogen receptor degrader (SERD), with HER2-targeted therapies including trastuzumab, trastuzumab-emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs). The combination of Amc and anti-HER2 therapies was investigated in a panel of four HER2+/ER+ cell lines: BT-474, MDA-MB-361, EFM-192a and a trastuzumab-resistant variant BT-474-T. Proliferation (IC50 and matrix combination assays) was determined using acid phosphatase assays. HER2/ER and intracellular signalling pathway protein levels/activity were investigated by western blot. Apoptosis was assessed using caspase 3/7 assays. Additivity and synergy were observed between Amc and the TKIs neratinib, lapatinib and tucatinib in all cell lines. Amc increased the anti-proliferative effect of trastuzumab in MDA-MB-361 and BT-474-T. Addition of Amc also increased anti-proliferative efficacy of T-DM1 in BT-474-T. TKI/Amc combinations reduced p-HER2 and ER levels and resulted in increased apoptosis. Higher ER expression in MDA-MB-361 and BT-474-T was associated with greater potential for synergy. In conclusion, the combination of Amc- and HER2-targeted treatments has potential as a therapeutic strategy for the treatment of HER2+/ER+ breast cancer and warrants further clinical investigation to validate safety and efficacy in patients.
Insights
Combining amcenestrant (Amc), a selective estrogen receptor degrader, with HER2-targeted therapies shows promise for HER2+/ER+ breast cancer. This preclinical study found synergistic effects, suggesting a new therapeutic strategy for this unique breast cancer subtype.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2-positive/oestrogen receptor-positive (HER2+/ER+) breast cancer is a distinct subtype.
- Therapeutic resistance can arise from compensatory crosstalk between HER2 and ER pathways.
- Novel combination therapies targeting both HER2 and ER are needed to improve patient outcomes.
Purpose of the Study:
- To explore the preclinical rationale for combining amcenestrant (Amc), a selective estrogen receptor degrader (SERD), with HER2-targeted agents.
- To evaluate the efficacy of Amc in combination with trastuzumab, trastuzumab-emtansine (T-DM1), and HER2 tyrosine kinase inhibitors (TKIs).
- To investigate the impact of these combinations on proliferation, signaling pathways, and apoptosis in HER2+/ER+ breast cancer models.
Main Methods:
- Utilized a panel of four HER2+/ER+ breast cancer cell lines, including a trastuzumab-resistant variant.
- Assessed cell proliferation using IC50 and matrix combination assays (acid phosphatase assay).
- Analyzed protein levels and signaling pathway activity (HER2, ER, p-HER2) via Western blot and apoptosis via caspase 3/7 assays.
Main Results:
- Amcenestrant demonstrated additive and synergistic effects with HER2 TKIs (neratinib, lapatinib, tucatinib) across all tested cell lines.
- The combination of Amc with trastuzumab enhanced anti-proliferative effects in specific cell lines (MDA-MB-361, BT-474-T).
- Amc combined with T-DM1 improved anti-proliferative efficacy in the trastuzumab-resistant BT-474-T cell line, with higher ER expression correlating with greater synergy.
Conclusions:
- The combination of amcenestrant with HER2-targeted therapies presents a promising therapeutic strategy for HER2+/ER+ breast cancer.
- These preclinical findings support further clinical investigation to establish the safety and efficacy of Amc-based combinations.
- Targeting both ER and HER2 pathways simultaneously may overcome resistance mechanisms and improve treatment outcomes.
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