Abstract 3479: Functional significance of ESR1 fusions with diverse gene partners in endocrine therapy resistant breast cancer

Abstract

Abstract Emerging evidence suggests that ESR1 fusion transcripts that produce functional fusion proteins in estrogen receptor positive (ER+) breast cancer play a role in acquired endocrine therapy resistance. We recently reported two in-frame ESR1 fusion transcripts, ESR1-YAP1 and ESR1-PCDH11X, identified in patients with endocrine therapy resistant breast cancer. Both ESR1 fusions generated stable in-frame, fusion proteins that were transcriptionally active, driving endocrine therapy resistant proliferation and also promoting an epithelial-to-mesenchymal transition (EMT) transcriptional program leading to metastasis in experimental models. Here, we extend our studies by examining properties of additional ESR1 fusions with diverse partner genes, ESR1-DAB2, ESR1-GYG1, ESR1-SOX9, ESR1-ARNT2, ESR1-PCMT1, and ESR1-ARID1B, all identified in endocrine-refractory breast tumors, to better understand the role of ESR1fusion gene formation in endocrine therapy resistance. Structurally, ESR1-ARNT2, ESR1-PCMT1, and ESR1-ARID1B fusions retain the first 6 exons of ESR1, therefore lacking ESR1 exons encoding the ligand-binding domain (LBD) that endocrine therapies recognize, but are instead fused in-frame to C-terminal sequences from partner genes, which follows the same fusion pattern of previously identified ESR1-YAP1, ESR1-PCDH11X, ESR1-DAB2, ESR1-GYG1, and ESR1-SOX9 fusions. ESR1-ARNT2, ESR1-PCMT1, and ESR1-ARID1B constructs, along with ESR1-DAB2, ESR1-GYG1, and ESR1-SOX9 constructs were stably expressed in an ER+ breast cancer cell line, T47D, and all produced stable fusion proteins. ESR1-ARNT2 and ESR1-SOX9 promoted hormone-independent and fulvestrant-resistant cell proliferation that was sensitive to cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib. In addition, ESR1-ARNT2 induced hormone-independent activation of estrogen responsive genes (TFF1, GREB1, and PGR), and EMT genes (SNAI1 and VCAN) along with upregulation of Snail protein. These results indicate that ESR1-ARNT2 and ESR1-SOX9 have similar functional and pharmacological properties to our previously described ESR1-YAP1 and ESR1-PCDH11X fusions. These data further support a role for ESR1 fusions in driving not only endocrine therapy resistance but also activating the metastatic process. Ongoing studies are examining the ability of ESR1 fusions to induce EMT phenotypes and to determine structure function relationships of ESR1 fusions. Although the formation of ESR1 fusions likely confers resistance to all endocrine therapies that target the LBD, ESR1 fusion driven growth remained sensitive to CDK4/6 inhibitor treatment therefore providing rationale for testing ESR1 fusion detection in guiding treatment with CDK4/6 monotherapy. Citation Format: Jonathan T. Lei, Xuxu Gou, Sinem Seker, Vaishnaivi Devorakonda, Kimberly R. Holloway, Adrian V. Lee, Dan R. Robinson, Matthew J. Ellis. Functional significance of ESR1 fusions with diverse gene partners in endocrine therapy resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3479.