Abstract PS17-52: A preclinical platform of breast cancer PDX-derived cell lines as a tool for pharmacological screening and functional studies

Abstract

Abstract Despite considerable progress in understanding the biology and genetics of breast cancer progression, the development of effective therapies need physiological and predictive preclinical models. In this context, breast cancer patient-derived xenograft (PDX) models has become a standard tool as they reproduce accurately the behavior of tumor of origin, in term of histological and molecular phenotype and response to chemotherapy. Although PDXs in vivo models are indispensable for preclinical studies, they suffer from some limitations due to study costs related to tumor maintenance on mice, variable engraftment rate, growth delay and limited throughput for large-scale drug screening.To address this problem and propose a time and cost effective preclinical screening tool, we developed a panel of breast cancer PDX-derived low-passage 2D cell lines as a convenient in vitro pre-screening platform to profile compound activity.30 different breast cancer PDX models including TNBC, HER2+ and ER+ were tested for their capacity to generate cell lines maintaining the characteristics of the parental PDX tumor and usable for in vitro assays.Today, we succeeded with a series of 14 PDX models.Tumor cells isolated from PDX tumor tissue were cultured under different media and matrix conditions, allowing at least 5 passages in culture. A Short Tandem Repeat (STR) comparison profile was done with the parental PDX before performing a master bank. We succeeded in establishing a panel of 14 PDX-derived cellular models (14/30 = 46% success rate).We performed short term 2D cytotoxicity assays and long term colony assays to compare cell lines in vitro drug sensitivity with their parental PDX in vivo drug response and overall, the results show that this panel reproduced the drug response profile of the original PDXs with chemotherapies, PARP inhibitors, an ADC (T-DM1) therapies.Moreover, cellular models engrafted back onto mice showed in vivo response to chemotherapies similar to that of the parental PDX confirming the identical behavior of cell line / PDX couples.As the use of cellular models is still considered as a standard for early preclinical test to evaluate drug response before moving to in vivo assays, our breast cancer PDX-derived cell line platform appeared to be a robust and relevant tool. Furthermore, since the main concern when using in vitro models is the representativeness of the results obtained when transposed to in vivo models, the similarities between cell lines and parental PDX should maximize success of further in vivo preclinical drug development. Citation Format: Stefano Cairo, Olivier Deas, Sophie Banis, Kathleen Flosseau, Enora Le Ven, Jean-Gabriel Judde. A preclinical platform of breast cancer PDX-derived cell lines as a tool for pharmacological screening and functional studies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-52.