SUN-006 Lasofoxifene Achieves Potent Anti-Tumor Activity in Hormone-Resistant Breast Tumors by Maintaining High Affinity Binding for Y537S ERα

Activating somatic mutations to the ligand binding domain (LBD) of ESR1 (the gene for estrogen receptor alpha) may arise after prolonged hormone treatments. Y537S and D538G are the most prevalent mutations, accounting for 16% and 32% of cases respectively. Both mutations resist tamoxifen by favoring the receptor’s active state in the absence of hormone to reduce the selective estrogen receptor modulator’s binding affinity. Fulvestrant, a selective estrogen receptor degrader, is the only clinically approved molecule that can fully ablate Y537S estrogen receptor alpha (ERα) transcriptional activity, but does so at decreased potency due to a reduced ligand binding affinity. Interestingly, lasofoxifene, a selective estrogen receptor modulator, possesses significant anti-tumor activity in preclinical models of luminal breast cancers harboring WT, Y537S, and D538G ERα. Comprehensive structural and biochemical studies were undertaken to determine the molecular basis for lasofoxifene potency towards Y537S ERα. X-ray crystal structures of lasofoxifene in complex with WT and Y537S ERα LBD show that the molecule adopts an identical conformation within the hormone binding pocket. While, a competitive ligand binding assay shows that lasofoxifene possesses the same affinity towards WT and Y537S ERα LBD in vitro, compared to 5-10 fold decrease compared to other SERMs and SERDs. Collectively, these data suggest that lasofoxifene achieves improved anti-tumor activity by retaining its high affinity binding for the Y537S ERα somatic mutant.