Aptamer Proteolysis-Targeting Chimeras (PROTACs): A Novel Strategy to Combat Drug Resistance in Estrogen Receptor α-Positive Breast Cancer.

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.