Abstract P119: Differential sensitivity to poly(ADP-ribose) polymerase inhibitors in patient-derived cell models of breast cancer

Abstract

Abstract Female breast cancer (BC) became the most commonly diagnosed cancer globally in 2020. One of the hallmarks of BC is both intratumor and intertumor heterogeneity. Efforts have been made to categorize this heterogeneity based on the presence or absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/ERBB2). Receptor expression patterns are used to stratify BC and the subsequent treatments. Much of the current knowledge of breast cancer comes from in vitro and in vivo studies using well established cell lines, some of which have been cultured since the 1950s. Given that serial passaging over many years has been reported to alter the mutational profile of cell lines and therefore their relevance to clinical decisions on the primary tumour, new near-tumor cell models need to be generated. In this study, tumour biopsies or ascitic fluids were obtained from a local cancer research biobank, as well as directly from metastatic BC patients across the globe. Using mechanical dissociation and cell separation techniques we isolated tumor cells and grew them in proprietary media. The resultant models were subjected to whole exome and RNA sequencing. In addition, the models were tested in a 3-day cell death assay against a library of more than 50 FDA-approved drugs. The models and four BC cell lines (HCC1937, ZR-75-1, MDA-MB-436 and HCC1428) were also tested in a longer term 7-day assay against a panel of four poly(ADP-ribose) polymerase (PARP) inhibitors. A total of 10 patient-derived cell (PDC) models were successfully established from biopsies or ascitic fluids taken from patients with primary (1/10) or metastatic (9/10) BC. Models were established from patients with ER+ BC, HER2+ BC and triple negative BC (TNBC) within an average of 23 days from sample arrival. All models displayed a greater sensitivity to the non-targeted drugs in the library compared with the targeted drugs. Mutations in breast cancer associated 1 (BRCA1) and BRCA2 genes that were not present in BC cell lines were identified in a subset of the PDCs. All models showed some sensitivity to PARP inhibitors, and most were exquisitely sensitive to talazoparib with IC50s of less than 100 nM. Determining cell death responses in near-tumour PDCs should thus be adopted to enable more informed clinical decisions for treatment pathways and in parallel will be promising tools for oncology drug discovery. Citation Format: Immaculate Nalubowa, Subir Singh, Yuen Ngan Fan, Rachel Howard-Jones, Albert Bezman, Dominic I. James, Geoff Muckle, Gareth J. Griffiths. Differential sensitivity to poly(ADP-ribose) polymerase inhibitors in patient-derived cell models of breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P119.