Molecular pharmacology of SERDs in the setting of tamoxifen resistance
Molecular pharmacology of SERDs in the setting of tamoxifen resistance
Molecular pharmacology of SERDs in the setting of tamoxifen resistance. Upon binding tamoxifen, ERα undergoes a specific conformational change that enables the presentation of protein-protein interaction surfaces for which in tamoxifen-sensitive cells there are no compatible coregulators. Thus, tamoxifen binding commits ER down a "nonproductive" pathway, an activity that manifests as antagonism. It is proposed that chronic administration of tamoxifen, however, results in the selection of a subpopulation of cells that express a compatible coactivator (CoA). In this manner the pharmacology of tamoxifen "switches" from that of an antagonist to an agonist. SERDs, like GDC-0810, have activity in the setting of tamoxifen resistance because they (a) function as high affinity competitive antagonists, (b) induce a conformational change that is incompatible with coregulator interactions, and (c) target the receptor for proteasomal degradation.