Fig. 1

Mechanisms of resistance of ESR1 mutations. a Mutations and effects. All ESR1-MUT mutations are in the LBD. Mutations stabilize the active conformation in the absence of ligand, decreasing affinity for ligands, including estrogen, SERMs, and SERDs. This results in constitutive activity, increased basal activity, and proteolytic stability, enhancing cancer growth, metastasis, and resistance. E2: estradiol, AF-1: activation function 1 domain, LBD: ligand-binding domain, AF-2: activation function 2 domain, DBD: DNA-binding domain. b Key targeted pathways in HR-positive breast cancer and effects of ESR1-MUT. In the ESR1-WT situation, AI depletion of estrogen inhibits ESR1 activity, SERMs such as tamoxifen alter ESR1 binding partners and transactivation ability, and SERDs such as fulvestrant inhibit ESR1 activity and proteolytic stability. PI3Ki and mTORC1i inhibit upstream phospho-activation of ESR1 and additional growth-promoting signaling, and CDK4/6i inhibits the cell cycle machinery downstream of PI3K, mTORC1, and ESR1 signaling. In the ESR1-MUT situation, AI is ineffective since ESR1-MUT does not require estrogen, and tamoxifen and fulvestrant bind less strongly to ESR1-MUT (novel drugs in these categories are subject to ongoing study). PI3Ki and mTORC1i theoretically remain effective, although the crosstalk between ESR1-MUT and PI3K/mTORC1 signaling is not known. CDK4/6i is effective in both ESR1-WT and ESR1-MUT breast cancer. TF: transcription factor