Drug-Conjugated Tam-NHC-Gold(I) Complexes Overcome <i>ESR1</i> Mutant Breast Cancer Resistance and Downregulate the RAMP3/CALCR Signaling Pathway

Endocrine resistance remains a major obstacle in the effective treatment of hormone-receptor-positive breast cancer. ESR1 mutations, such as Y537S and D538G, are commonly considered to confer such resistance. It is necessary to develop novel therapeutic agents to overcome endocrine resistance. Herein, we developed drug-conjugated Tam-NHC-gold(I) complexes that can target breast cancer cells by the binding of tamoxifen (Tam) to the G protein-coupled estrogen receptor (GPER) present on cell membranes. The privileged complex, 7b, can significantly downregulate ER, inhibit ER downstream signaling pathways, and induce damage-associated molecular pattern (DAMP)-mediated immunogenic cell death (ICD). Mechanistically, RNA-sequencing analysis revealed that 7b can overcome mutant MCF-7 Y537S resistance through the RAMP3/CALCR signaling pathway. Moreover, 7b exhibited potent antiproliferative activity on both wild-type and mutant MCF-7 Y537S in xenograft mouse models with low toxicity. This study verified that 7b may offer a new approach for the treatment of endocrine-resistant breast cancer.