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Aptamer Proteolysis-Targeting Chimeras (PROTACs): A Novel Strategy to Combat Drug Resistance in Estrogen Receptor
Ying Feng1, Zhilin Zhang1, Haowei Zhang1
1State Key Laboratory of Chemical Oncogenomics, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Abstract:
Breast cancer with positive expression of estrogen receptor α (ERα+) accounts for 70% of breast cancer cases, whose predominant treatment is currently endocrine therapy. The main strategy of endocrine therapy for ERα+ breast cancer is to inhibit the ERα signaling pathway and downregulate ERα levels, which often results in mutations in the ligand-binding domain (LBD) of ERα, leading to significant resistance to subsequent treatment in patients. To combat drug resistance, we first proposed a novel aptamer PROTAC strategy through specifically targeted degradation of ERα via targeting the DNA-binding domain (DBD) of ERα. We proved that this strategy is capable of targeting ERα for degradation through ubiquitination, leading to the inhibition of proliferation in ERα+ breast cancer cells and tamoxifen-resistant breast cancer cells. Furthermore, we investigated the mechanisms involved in overcoming resistance. By circumventing drug resistance associated with LBD mutations in ERα, our approach provides a promising avenue for the discovery of new therapeutic agents.
Insights
A new aptamer PROTAC strategy targets estrogen receptor alpha (ERα) degradation in ERα+ breast cancer. This approach overcomes endocrine therapy resistance caused by ERα mutations, offering a promising new treatment avenue.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Estrogen receptor alpha-positive (ERα+) breast cancer constitutes 70% of cases, primarily treated with endocrine therapy.
- Endocrine therapy resistance frequently arises from mutations in the ERα ligand-binding domain (LBD).
Purpose of the Study:
- To develop a novel therapeutic strategy targeting ERα for degradation in ERα+ breast cancer.
- To overcome endocrine therapy resistance mediated by ERα LBD mutations.
Main Methods:
- Development of an aptamer PROTAC (proteolysis-targeting chimera) strategy.
- Targeting the DNA-binding domain (DBD) of ERα for degradation via ubiquitination.
Main Results:
- The aptamer PROTAC strategy successfully induced ERα degradation through ubiquitination.
- Inhibition of proliferation was observed in both ERα+ breast cancer cells and tamoxifen-resistant cells.
- The mechanism circumvents resistance associated with ERα LBD mutations.
Conclusions:
- The novel aptamer PROTAC strategy effectively degrades ERα, overcoming endocrine resistance.
- This approach presents a promising new therapeutic avenue for ERα+ breast cancer, particularly in cases of drug resistance.
