Abstract 2122: Generation of a fully characterized preclinical PDX panel to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies

Abstract

Abstract The last 20 years have witnessed the identification of an increasing number of actionable oncogenic drivers and the development and clinical use of specific inhibitors against these targets. Unfortunately, patients treated with targeted therapies consistently develop resistance and progression under treatment. Hence, important scientific, pharmaceutical and medical research efforts are directed towards understanding the mechanisms of acquired resistance to explore new therapeutic pathways. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be fully characterized at molecular and pharmacological level and used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Acquired Resistance) models is planned over 3 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. To favor successful xenograft establishment, the first two passages are performed without drug treatment, which is applied from the third passage on. When doing so, we observed 3 types of response: some models showed resistance from the first passage under treatment, some showed stabilization under treatment at the first passages and rapidly acquired resistance over passages, and others showed sensitivity to treatment, whereas the patient tumor showed progression under the same treatment. These different behaviors might be due to different mechanisms of resistance, irreversible for the former, reversible for the two latter, as well as to suboptimal correlation of the clinical dose with the one used in mice. An example of such discrepancies has been found in two models of NSCLC PDX obtained from two metastases from a patient treated by a ROS1 and ALK inhibitor. While LCx-MR135PD2-AR PDX does not respond to the treatment, the LCx-MR135PD1 model is highly sensitive. As both metastases were progressing under treatment in the patient, molecular and pharmacological comparative analysis of these two models will investigate these discrepancy and provide important insights into the mechanisms of resistance to such inhibitors. Overall, the MatchR PDX project will provide a unique preclinical platform to identify resistance mechanisms to current targeted therapies and to develop next generation therapeutic strategies. Citation Format: Olivier Déas, Ludovic Bigot, Emilie Dasse, Guillaume Lang, Yohann Loriot, Fabrice Andre, Jean-Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Jean-Gabriel Judde, Luc Friboulet. Generation of a fully characterized preclinical PDX panel to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies [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 2122.