Abstract 3810: Establishment of an in vitro assay that phenocopies tumor response to PARP inhibitors in vivo

Abstract

Abstract Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have recently emerged as therapeutic options for patients with homologous recombination-deficient (HRD) breast or ovarian cancer, two heterogeneous diseases associated with high mortality rates. As shown in several clinical studies, patient response to PARPi is invariably followed by eventual mid-long term resistance and progression under treatment. The molecular processes contributing to PARPi-resistance are at present under-explored. Therefore, a huge effort is being made to better understand how to overcome resistance and to identify ad-hoc combinations with other targeted therapies to improve tumor response and extend progression-free survival. We have previously published the PARPi-response profile of a panel of 40 breast cancer (BC) patient-derived xenografts (PDXs). The models tested showed heterogeneous response to PARPi, and only partial association with the genomic status of BRCA genes, the only currently acknowledged clinical marker to select patients that can benefit from PARPi administration. Although these models are ideal preclinical tools for the evaluation of drug combinations to improve tumor response to PARPi as single agent, the use of these models for early preclinical evaluation of combination efficacy is not straightforward in reason of the limited throughput and of the ethical issue with respect of the 3Rs. The use of cellular models is still considered as a standard early preclinical test to evaluate drug response before moving to in vivo assays. However, the main concern when using in vitro models is the representativeness of the results obtained when transposed to in vivo models. In this study, we have setup an in vitro assay that recapitulates the response to PARPi observed in vivo in our BC PDXs, with particular focus on the models that show resistance to PARPi. To this aim we generated 9 cellular models from 9 BC PDX models: HBCx-2, HBCx-3, HBCx-6, HBCx-8, HBCx-9, HBCx-17, HBCx-19, HBCx-39 and T174. Two cellular models (HBCx-3, and HBCx-19) were established from ER+ BC PDX and 7 from ER- BC PDXs and two models, HBCx-8 and HBCx-17, harbor BRCA1 and BRCA2 mutation, respectively. Seven out of 9 models are resistant to PARPi in vivo, with HBCx-6 PDX showing partial tumor regression and HBCx-17 PDX showing tumor stabilization upon treatment. Several different 2D-culture experimental conditions, namely different cell growth conditions, drug concentrations, duration of cell exposure to drugs, time points and readouts, have been tested to evaluate response to olaparib. The results showed that a 2D colony assay is the best experimental strategy to faithfully evaluate tumor cell sensitivity, minimizing the false positive results when compared to the in vivo data.. This cell panel will be used to identify combination of PARPi with a library of FDA-approved targeted therapy to identify the treatments to be moved forward in vivo. Citation Format: Olivier Déas, Romain Rousseau, Sophie Banis, Kathleen Flosseau, Enora Le Ven, Jean-Gabriel Judde, stefano cairo. Establishment of an in vitro assay that phenocopies tumor response to PARP inhibitors in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3810.