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Pre-Clinical rationale for amcenestrant combinations in HER2+/ER+ Breast cancer

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posted on 2025-01-31, 08:49 authored by Amira MahdiAmira Mahdi, Niall Ashfield, John Crown, Denis M. Collins

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.

History

Publication

International Journal of Molecular Sciences 26(2), 460

Publisher

MDPI

Other Funding information

Science Foundation Ireland Strategic Partnership Programme Award ACORN (20-SPP-3684) Puma Biotechnology Irish Research Council Postgraduate Enterprise Partnership Scheme, in conjunction with the Cancer Clinical Research Trust (EPSPG/2021/243). D.M.C. was funded by The Caroline Foundation and the Cancer Clinical Research Trust (Charity No. CHY12210)

Department or School

  • School of Medicine

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