Patient-Derived Xenograft Study Reveals The Pharmacology And The Role Of Esr1 Gene Aberrations In Endocrine Therapy Resistance Of Er Positive Breast Cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: The study of estrogen-receptor-positive patient-derived xenografts (PDXs) from patients with disease progression despite endocrine therapy has revealed recurrent ESR1 mutation, gene amplification and ESR1 gene translocations as likely drivers of resistance. We addressed this hypothesis further using pharmacological and genetic approaches in the PDX system. Methodology: ER positive PDXs that harbored one of four recurrent ligand binding domain (LBD) mutations (Y537S/N/C and D538G) as well as a ESR1/YAP1 translocation were studied in parallel with T47D and MCF7 cells expressing these mutants through lentivirus constructs. Single cell suspensions generated from PDX models were using for in vitro experiments using with a panel of endocrine inhibitors and ESR1 shRNA constructs. In vitro effects were confirmed using in vivo tumor response. Results: Cell suspensions from ER+ PDX models in short-term culture successfully reproduced the endocrine therapy resistant phenotypes exhibited by the donor patient, thereby facilitating drugs screens designed to identify new endocrine approaches for ESR1 mutant breast cancer using authentic models rather than an exclusive reliance on models derived by transfection of mutant constructs into standard indicator cell lines. We were also able to demonstrate that that lentivirus-driven shRNA mediated knockdown of ESR1-YAP1 caused inhibition of PDX tumor growth in in vivo and reduced cell growth in vitro, confirming that this chimeric protein is a driver of estradiol-independent growth. Conclusion: ER+ PDX can be manipulated in vitro and in vivo to successfully model ESR1 mutation and gene-rearrangement driven endocrine therapy resistance. PDX studies complement standard ectopic expression systems for the study of ESR1 mutation-driven resistance and, we hypothesize, will provide pharmacological data that will predict the activity of pharmacological agents designed to improve outcomes for patients with ESR1 mutant driven endocrine therapy resistance. Citation Format: Triparna Sen, Shunqiang Li, Jieya Shao, Robert Crowder, Robert Kitchens, Matthew J. Ellis. Patient-derived xenograft study reveals the pharmacology and the role of ESR1 gene aberrations in endocrine therapy resistance of ER positive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5544. doi:10.1158/1538-7445.AM2014-5544