Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies
Estrogen receptor-positive (ER+) breast cancer accounts for approximately 75% of all breast cancer cases. Endocrine therapies, including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor down-regulators (SERDs), have proven effective in reducing the risk of disease recurrence and mortality in ER+ breast cancer. However, resistance to these therapies remains a significant challenge, limiting the success of treatment for ER+ breast cancer patients.
Endocrine resistance arises through various mechanisms, including alterations in estrogen receptor (ER) signaling (e.g., ER downregulation, ESR1 mutations or fusions), changes in ER coactivators and corepressors, transcription factors (TFs), nuclear receptors, and epigenetic modulators. Additional contributing factors include the dysregulation of key signaling pathways, modulation of cell cycle regulators, stress signaling, and changes in the tumor microenvironment, nutrient stress, and metabolic regulation.
To address endocrine resistance, current clinical strategies focus on targeting pathways such as mechanistic target of rapamycin (mTOR), cyclin-dependent kinase 4/6 (CDK4/6), and the phosphoinositide 3-kinase (PI3K) subunit p110α. Preclinical studies have identified several novel therapeutic targets, many of which are being tested in clinical trials as single agents or in combination with endocrine therapies. These include ER partial agonists, ER proteolysis-targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, dual inhibitors of epidermal growth factor receptor 1 and 2 (EGFR/HER2), HER2-targeting antibody-drug conjugates (ADCs), and histone deacetylase (HDAC) inhibitors.
In this review, we provide an overview of the established and emerging mechanisms of endocrine resistance, the alterations that occur during metastatic recurrence, and discuss the current approved therapies as well as ongoing clinical trials that are testing novel targeted therapies in combination with endocrine therapy BSJ-03-123 for patients with endocrine-resistant ER+ breast cancer.