Therapeutic Strategies to Target Activating Estrogen Receptor α Mutations

Breast cancer is a hormone-dependent disease. Despite great strides, estrogen receptor α (ER)-positive breast cancer remains a challenging disease. About 60–70% of breast cancers are ER positive, which is predictive of response to endocrine therapies, including selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). However, many patients will still develop therapeutic resistance. One mechanism of resistance is the development of gain-of-function mutations in the ligand-binding domain (LBD) of ER. Mutant ER exhibits ligand-independent, pro-metastatic activity, and higher concentrations of antiestrogens are required to inhibit its activity. Fulvestrant, currently the only FDA-approved SERD, possesses dose-limiting pharmacological properties and promotes only partial degradation of ER. New orally bioavailable SERMs and SERDs are being developed to overcome the shortcomings of current mainstay treatments but are challenging classes of drug to develop. Taking a ligand-binding domain-independent approach by modulating molecular chaperones and E3 ligases that control ER stability could be an alternative approach to circumvent endocrine resistance and could also be used to target additional oncogenic drivers in mutant ER tumors.