Abstract A017: Development and characterization of HER2+ T-DM1-resistant breast PDX models in athymic nude mice

Abstract

Abstract Background: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for treatment of HER2 positive (HER2+), trastuzumab-resistant breast cancers. While this agent is initially effective, resistance often develops. To aid in developing new therapies for HER2+, T-DM1-resistant breast cancer and better understanding resistance mechanisms, we established PDX models designated ST340, ST1339, and ST2167 from three patients with trastuzumab-resistant HER2+ breast cancer and sensitive to T-DM1 treatment in vivo. A cohort of each model was conditioned in vivo with chronic T-DM1 treatment to generate drug resistance. These models, designated ST340/TDR, ST1339/TDR, and ST2167/TDR were subjected to characterization and efficacy studies, and the results compared with parent models. Methods: ST340, ST1339, and ST2167 were established from patients who responded then progressed on trastuzumab and other therapies. The models were passaged, and cohorts were challenged with chronic T-DM1 treatment to produce drug resistance. The parent and resistant models were subjected to various comparative analyses including receptor expression, RNAseq, and response to various relevant therapies. Results: T-DM1-resistant models retained high HER2 expression and demonstrated receptor staining and histopathology comparable to respective parent lines. Comparison of parent and resistant clones using RNAseq identified several alterations in variants and expression. In vivo T-DM1 reported significant activity towards ST340: %T/C=3%, ST1339: %T/C=-40% and ST2167: %T/C=13% versus control, including tumor regressions in ST1339. T-DM1-resistant models reported the following values following treatment: ST340/TDR: %T/C=65%, ST1339/TDR: %T/C=58% and ST2167/TDR: T/C=91%. Conclusion: We have established and characterized three paired T-DM1-sensitive and resistant breast PDX models, which can be utilized as valuable tools in developing new therapies for T-DM1-resistant patients. Citation Format: Alyssa Moriarty, Lizette Gamez, Tomoyuki Mashimo, Kyriakos Papadopoulos, Amita Patnaik, Drew Rasco, Amy Lang, Ronald Drengler, Michael J Wick. Development and characterization of HER2+ T-DM1-resistant breast PDX models in athymic nude mice [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A017. doi:10.1158/1535-7163.TARG-19-A017