Abstract A083: A breast cancer PDX-derived cell lines preclinical platform as a tool for pharmacological screening and functional studies

Abstract

Abstract Breast cancer (BC) is a heterogeneous disease that likely originates from different cell compartments that co-inhabit the mammary gland, with more than 20 different histology types reported. At molecular level, BCs are classified by immunohistochemistry as luminal if estrogen and/or progesterone receptor (ER and PR) are over-expressed, HER2-positive if they over-express HER2/neu receptor (encoded by ERBB2, a known proto-oncogene), or triple negative (TN) when ER and PR are not expressed with HER2 being expressed at (sub-)normal levels. The availability of an increasing number of very well molecularly annotated BC samples allows an unprecedented stratification of this disease, with numerous gene signatures published in recent years that identified additional mutational landscape and/or signaling pathway-based molecular subtypes. Despite this considerable progress in understanding the biology and genetics of this disease, the development of effective therapies is hampered by the lack of sufficient experimental models that recapitulate the genetic diversity of this disease. To tackle this issue, over the last 15 years, we have generated and well characterized a collection of 40+ breast cancer patient-derived xenografts (PDXs) that accurately reproduce BC histological and molecular heterogeneity. This preclinical panel is currently used to validate candidate anticancer drugs and has allowed for the preclinical evaluation of several drugs that are now used in the clinic. Although being an indispensable tool to complete preclinical studies, the use of PDX in vivo systems for large-scale screening during early drug discovery is hampered by ethical and economical burdens limiting the number of test articles being tested. To address this problem, we developed a panel of BC PDX-derived cell lines (PDXDCs) that we offer as a cost-effective and rapid preclinical screening tool to profile the anti-cancer activity of early test articles in medium-throughput. To date, 14 PDXDCs from various BC PDXs including TNBC, HER2+ and ER+ have been generated and tested for their in vitro response towards known anti-BC agents, used as monotherapy or in combination to study possible synergistic effects. In parallel to PDXDCs RNA/WES sequencing data matching well with the parental PDX features, we also could phenocopy in vitro the corresponding PDXs’ sensitivities to chemotherapies, PARP inhibitors, antibodies and ADC (T-DM1) therapies. These results support our PDXDCs panel as valuable in vitro tool for drug screening to help selecting drug candidates to be further validated in vivo. Citation Format: Kathleen Flosseau, Léa Sinayen, Enora Le Ven, Emilie Indersie, Ester Morgado, Laurent Pouyet, François Romagné, Olivier Déas. A breast cancer PDX-derived cell lines preclinical platform as a tool for pharmacological screening and functional studies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A083.