Defining the molecular pharmacology of disease relevant estrogen receptor mutations for effective therapeutic targeting in breast cancer (2019)

The Estrogen Receptor (ER/ ESR1 ) is expressed in the majority of luminal breast cancers and drugs that inhibit ER‐signaling, (e.g. the Selective Estrogen Receptor Modulator (SERM) tamoxifen and aromatase inhibitors like letrozole, or anastrozole) are the cornerstone of breast cancer pharmacotherapy. However, in the adjuvant setting, the clinical success of these drugs are limited by the development of resistance. Whereas the mechanisms underlying resistance are varied and complex, it is now clear that gain of function point mutations within the ligand binding domain (LBD) of ESR 1 likely contribute to the development of resistance to aromatase inhibitors. Although extremely rare in primary breast tumors, mutations in the ESR1 LBD occur in up to 40% of metastatic lesions. Preclinically, it has been demonstrated that these mutations drive ER− dependent transcription, proliferation and tumor cell migration in the absence of hormone. Importantly, several reports have demonstrated that these mutant ERs may display resistance to standard hormonal therapies, a finding which defines the need for new antiestrogens. The goal of this study is to understand the molecular basis for the altered pharmacology of the most clinically relevant ESR1 mutations and to use this information to inform the selection of new or existing drugs that would be expected to inhibit the activity of these receptors. In cell based models of breast cancer, we made the important observation that when compared to wild‐type ER, the pharmacology (most notably potency) of these mutants was significantly impacted by cell context and receptor expression level. This was apparent in assays that measured ER‐transcriptional activation and cell proliferation. Specifically, although we and others have observed that the potency of existing ER antagonists are reduced when ESR1 mutants are evaluated, such differences are dependent on the expression level of the receptors and are most apparent under conditions of overexpression. These data highlight the need to define the relationship between ER expression level and ligand potency/efficacy in the development of pharmaceutical approaches to target ESR1 mutants. Importantly, we observed that the potency and efficacy of lasofoxifene, a very high affinity SERM, did not differ significantly in any of the model systems studied. We believe that this activity of lasofoxifene can most likely be explained by its increased affinity as it was not shown to have any significant differences from other modulators in its ability to regulate ER stability or conformational state. This data suggest that the pharmacology of the most prevalent ESR1 mutants is dependent on both receptor expression level and cell context, and that these differences are not significant when a high affinity ER‐antagonist is employed. These findings have near term clinical implications for the treatment of endocrine therapy resistant breast cancers. Support or Funding Information Funding was provided by NIH R01 DK048807 (DPM) and the Pharmaceutical Sciences Training Program (T32 GM 007105) and NCI F31 CA220978‐01 (KJA) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .