Abstract P5-04-26: Identification of preclinical mechanisms driving acquired resistance to endocrine therapy in estrogen-receptor positive (ER+) breast cancer cells
Authors: Ong C , Daemen A , Merrick K , O'Brien T , Friedman L , Hatzivassiliou G 
Published: May 2019

Estrogen Receptor positive (ER+) breast cancer accounts for the majority of breast cancer cases and standard of care for these tumors is treatment with endocrine therapy, including the blockade of estrogen production (i.e. aromatase inhibitors; AIs) as well as the use of antagonists of ER function, i.e. selective estrogen receptor modulators (SERMs, i.e. tamoxifen) and selective estrogen receptor degraders (SERDs, i.e. fulvestrant). Despite the initial dependency of ER+ breast tumors on estrogen and ER for their survival and proliferation, treatment in the metastatic setting invariably leads to therapeutic resistance. While mechanisms of resistance to AIs include mutations in the estrogen receptor gene ESR1, less is known about mechanisms of resistance to SERMs and SERDs, thus it is essential to further investigate the latter, in order to successfully treat relapsed patients. To pre-clinically model cell-autonomous acquired resistance to these agents, we used T47D, an ER+ and p53- estrogen-responsive cell line treated with increasing concentrations of the SERM/SERD hybrid (SSH) ER-targeting agent GDC-0810 over the period of several months during which individual clones with acquired resistance to GDC-0810 were selected. GDC-0810-resistant clones were cross-resistant to other endocrine agents, including SERMs (tamoxifen) and SERDs (fulvestrant), consistent with general loss of dependency on ER. Surprisingly, the cells also lost sensitivity to palbociclib, the latter likely linked to their loss of one copy of the retinoblastoma (Rb) tumor suppressor gene. Comprehensive genetic and phenotypic characterization of the resistant clones relative to the parental cells revealed multiple mutations and deletions in DNA repair and cell cycle genes, and associated defects in DNA repair and cell cycle checkpoints. Cell cycle, proteomic, and mRNA expression analysis of parental versus resistant clones at baseline and upon DNA damage, identified a distinct cell cycle profile in the GDC-0810-resistant clones, characterized by accumulation of cells in the mitotic phase. A broad chemical screen identified pharmacologic inhibitors of cell cycle regulators and chemotherapeutic drug classes that preferentially target the ER-independent, GDC-0810 resistant clones compared to the parental cells. Our work provides novel insights into mechanisms and biomarkers of acquired resistant to estrogen therapies in ER+ breast cancer and reveals the acquisition of actionable dependencies that may potentially be exploited in resistant tumors. Furthermore, our studies provide rationale for testing specific chemotherapy regimens upon endocrine resistance accompanied by cell cycle and DNA repair checkpoint dysfunction in ER+ breast cancer.

Citation Format: Ong C, Daemen A, Merrick K, O'Brien T, Friedman L, Hatzivassiliou G. Identification of preclinical mechanisms driving acquired resistance to endocrine therapy in estrogen-receptor positive (ER+) breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-26.