Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.
Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.
“Stapled” peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl in the γ-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50 = 89 nM) replaces isoleucine 689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nM). Through x-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-γ-methyl peptide minimizes syn-pentane interactions between α- and γ-methyl groups.
Epigenetic regulators play key roles in cancer and are increasingly being targeted for treatment. However, for many, little is known about mechanisms of resistance to the inhibition of these regulators. We have generated a model of resistance to inhibitors of protein arginine methyltransferase 5 (PRMT5). This study was conducted in KrasG12D;Tp53-null lung adenocarcinoma (LUAD) cell lines. Resistance to PRMT5 inhibitors (PRMT5i) arose rapidly, and barcoding experiments showed that this resulted from a drug-induced transcriptional state switch, not selection of a preexisting population. This resistant state is both stable and conserved across variants arising from distinct LUAD lines. Moreover, it brought with it vulnerabilities to other chemotherapeutics, especially the taxane paclitaxel. This paclitaxel sensitivity depended on the presence of stathmin 2 (STMN2), a microtubule regulator that is specifically expressed in the resistant state. Remarkably, STMN2 was also essential for resistance to PRMT5 inhibition. Thus, a single gene is required for both acquisition of resistance to PRMT5i and collateral sensitivity to paclitaxel in our LUAD cells. Accordingly, the combination of PRMT5i and paclitaxel yielded potent and synergistic killing of the murine LUAD cells. Importantly, the synergy between PRMT5i and paclitaxel also extended to human cancer cell lines. Finally, analysis of The Cancer Genome Atlas patient data showed that high STMN2 levels correlate with complete regression of tumors in response to taxane treatment. Collectively, this study reveals a recurring mechanism of PRMT5i resistance in LUAD and identifies collateral sensitivities that have potential clinical relevance.
Significance: Bazedoxifene (BZA) is a potent orally available antiestrogen that is clinically 26 approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA 27 to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after 28 prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, 29 biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding 30 domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-31 hydroxytamoxifen.Abstract 42 Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer 43 patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα) gene ligand-binding 44 domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with 45 improved efficacy versus tamoxifen might overcome the resistant phenotype in ER+ breast 46 cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in 47 hormone replacement therapies. We find BZA possesses improved inhibitory potency against the 48 Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in 49 combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and 50 structural biology studies show that BZA's selective estrogen receptor degrading (SERD) 51 properties that override the stabilizing effects of the Y537S and D538G ERα mutations. 52 53 54 55 56 57 58 59 60 Fanning, S.W. eLife 3 61 Introduction 62 Estrogen receptor alpha (ERα) plays critical roles in the etiology, treatment and 63 prevention of the majority of breast cancers [1]. Due to the high degree of efficacy and wide 64 therapeutic indices of endocrine therapies, patients may receive such treatments for progressive 65 disease over the course of several years [2]. Unfortunately, the majority of ER+ metastatic breast 66 cancers that initially respond to endocrine treatment will become refractory despite continued 67 ERα expression [2]. Selective estrogen receptor modulators (SERMs) like tamoxifen are 68 antagonistic in the breast and agonistic in the bone and endometrium. SERM agonist activity 69 stems from tissue-specific co-regulator binding in the presence of tamoxifen [3]. In addition, 70 somatic mutations to ESR1 (gene for ERα) ligand binding domain (LBD) were identified in 25-71 30% of patients who previously received endocrine treatment [2, 4-6]. Y537S and D538G are the 72 two most prevalent mutations, and pre-clinical studies show that these mutations confer 73 hormone-free transcriptional activity and relative resistance to tamoxifen and fulvestrant 74 treatment [2, 4-6]. Both mutants enable constitutive ERα activity by favoring the agonist-like 75 conformation of the receptor activating function-2 (AF-2) surface and significantly reduce 76 hormone and 4-hydroxytamoxifen (the active metabolite of tamoxifen) binding affinities [7, 8]. 77 Endocrine treatments with im...
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