Background Despite considerable progress in understanding the biology and genetics of cancer, the development of effective therapies is hampered by the lack of sufficient experimental models that recapitulate the genetic diversity of this disease. The use of patient-derived xenograft (PDX) for the evaluation of new candidate anticancer drugs has become the gold standard in preclinical oncology. The faithful reproduction of patients’ cancer features, and the possibility to generate a large number of models that recapitulate patient population genetic heterogeneity, confer PDXs a critical added value in the evaluation of new drug candidates drugs. Over the last 15 years, we have generated and characterized a collection of 200+ PDXs from different solid tumors that accurately reproduce the histological and molecular heterogeneity of the tumors of origin. This panel has allowed for the preclinical validation of several anticancer drugs that are now used in the clinic. Although an indispensable tool for carrying out preclinical studies, the use of in vivo PDX systems for large-scale screening during early drug discovery is hampered by ethical, economic and throughput limiting the number of drug candidates tested.

Methods To address this problem, we developed a panel of PDX-derived cells (PDXDCs) that we propose as a time and cost-effective medium-throughput screening tool to profile the anti-cancer activity of early test compounds. PDXDC were obtained from dissociated PDX tumors cultured under various media and matrix conditions. They were characterized by comparison with the parental PDX by Short Tandem Repeat (STR) profiling before performing a master bank.

Results To date, 50+ PDXDCs from various indications such as breast, prostate, lung, and several others have been generated and tested for their response in vitro towards standards of care, targeted anti-cancer agents and immunotherapies, used as monotherapy or in combination to study possible synergistic effects. PDXDCs RNA and exome sequencing data faithfully match the parental PDX features, and by modulating experimental parameters, such as 2D or 3D growth conditions, drug exposure duration and endpoint read-outs, we could phenocopy in vitro the corresponding PDXs’ sensitivities to drug candidates.

Conclusions 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 as well as the most appropriate in vivo PDX models to be used.

Ethics Approval The animal care and housing are in accordance with French regulatory legislation concerning the protection of animals used for scientific purposes (agreement No. D-91-228-107) All experiments are performed in accordance with French legislation concerning the protection of laboratory animals and in accordance with a currently valid license for experiments on vertebrate animals, issued by the French Ministry of Higher Education, Research and Innovation. Project Agreement : APAFIS#30365-2021012215599431 v1.