Drug-Conjugated Tam-NHC-Gold(I) Complexes Overcome ESR1 Mutant Breast Cancer Resistance and Downregulate the
Yunlong Lu1, Lijuan Liu1, Zhenlin Liang1
1School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Abstract:
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-7Y537S resistance through the RAMP3/CALCR signaling pathway. Moreover, 7b exhibited potent antiproliferative activity on both wild-type and mutant MCF-7Y537S 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.
Insights
A novel gold(I) complex, 7b, targets endocrine-resistant breast cancer by downregulating estrogen receptor (ER) and inducing immunogenic cell death (ICD). This compound shows promise in preclinical models, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Medicinal Chemistry
- Cancer Immunology
Background:
- Endocrine resistance, often driven by ESR1 mutations (e.g., Y537S), hinders effective treatment for hormone-receptor-positive breast cancer.
- Developing novel agents to overcome endocrine resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To design and evaluate novel drug-conjugated Tam-NHC-gold(I) complexes targeting breast cancer cells.
- To investigate the efficacy of complex 7b in overcoming endocrine resistance and inducing immunogenic cell death (ICD).
Main Methods:
- Synthesis and characterization of Tam-NHC-gold(I) complexes.
- Assessment of complex 7b's ability to downregulate estrogen receptor (ER) and inhibit downstream signaling.
- RNA-sequencing analysis to elucidate the mechanism of action against mutant MCF-7Y537S cells.
- Evaluation of antiproliferative activity and toxicity in xenograft mouse models.
Main Results:
- Complex 7b effectively targets breast cancer cells via tamoxifen (Tam) binding to G protein-coupled estrogen receptor (GPER).
- 7b significantly downregulates ER, inhibits ER signaling, and induces damage-associated molecular pattern (DAMP)-mediated immunogenic cell death (ICD).
- RNA-sequencing identified the RAMP3/CALCR pathway as key to overcoming MCF-7Y537S resistance.
- 7b demonstrated potent antiproliferative activity against wild-type and mutant MCF-7Y537S in vivo with low toxicity.
Conclusions:
- Complex 7b represents a promising therapeutic strategy for endocrine-resistant breast cancer.
- The RAMP3/CALCR pathway is a potential target for overcoming resistance mediated by ESR1 mutations.
- Drug-conjugated gold(I) complexes offer a novel approach for treating resistant breast cancer phenotypes.
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