Pre-Clinical Rationale for Amcenestrant Combinations in HER2+/ER+ Breast Cancer
HER2-positive/estrogen receptor-positive (HER2+/ER+) breast cancer represents a distinct and challenging subtype of the disease. While targeting either the HER2 receptor or the estrogen receptor (ER) individually has shown therapeutic benefits, it can also lead to the development of resistance. This resistance arises due to compensatory receptor crosstalk, where the activation of one pathway may support the survival of cancer cells even when the other pathway is inhibited. To overcome this, there is increasing interest in exploring novel drug combinations that target both HER2 and ER pathways simultaneously. Such strategies could potentially improve clinical outcomes for patients with HER2+/ER+ breast cancer.
In this study, the pre-clinical rationale for combining amcenestrant (Amc), a selective estrogen receptor degrader (SERD), with existing HER2-targeted therapies was thoroughly investigated. Specifically, the study explored combinations of Amc with trastuzumab, trastuzumab-emtansine (T-DM1), and tyrosine kinase inhibitors (TKIs) such as neratinib, lapatinib, and tucatinib. The goal was to assess whether targeting both receptors in tandem would provide enhanced anti-cancer effects compared to monotherapy.
The combination therapies were tested in a panel of four HER2+/ER+ breast cancer cell lines: BT-474, MDA-MB-361, EFM-192a, and a trastuzumab-resistant variant, BT-474-T. To evaluate the efficacy of the combinations, cell proliferation assays (IC50 and matrix combination assays) were performed using acid phosphatase assays. Additionally, the levels and activities of key signaling proteins involved in HER2/ER pathways were analyzed through western blot techniques, and apoptosis was measured using caspase 3/7 assays.
The study revealed promising results. Additivity and synergy between Amc and the TKIs neratinib, lapatinib, and tucatinib were observed across all cell lines. Furthermore, the combination of Amc with trastuzumab enhanced its anti-proliferative effects, particularly in the MDA-MB-361 and BT-474-T cell lines, with Amc also boosting the efficacy of T-DM1 in the trastuzumab-resistant BT-474-T cells. Notably, the combination therapies reduced levels of phosphorylated HER2 (p-HER2) and ER, which are key markers of signaling activity in cancer cells, and led to a marked increase in apoptosis.
The study also found that higher levels of ER expression in MDA-MB-361 and BT-474-T cell lines were associated with greater potential for synergy between Amc and HER2-targeted therapies, suggesting that ER expression could be a predictor of the success of combination treatment.
In conclusion, the findings of this study highlight the potential therapeutic benefit of combining Amc with HER2-targeted therapies for the treatment of HER2+/ER+ breast cancer. This dual-target approach not only enhances the anti-proliferative effects but also promotes apoptosis in cancer cells, offering a promising strategy for overcoming resistance mechanisms. Further clinical investigations are warranted to validate the safety, efficacy, and potential clinical application of this combination therapy in patients with HER2+/ER+ breast cancer.