Abstract 3016: Identification of the mechanisms of resistance to targeted therapies in advanced solid cancers

Despite progress in understanding aberrations that contribute to the development and progression of cancer, resistance to classical chemotherapeutic agents or novel targeted drugs continues to be a major problem in cancer therapy. Hence, the identification of the mechanisms underlying drug resistance acquisition is the key to explore new and efficient therapeutic pathways for patients. 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 under treatment. 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 are being fully characterized at both molecular and pharmacological levels 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. To favor successful xenograft establishment, the first passages are performed without drug treatment, then all the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy. When applying therapeutic pressure, we observed different types of response: resistance from the first passage under treatment, stabilization under treatment at the first passages and rapidly acquired resistance over passages, or sensitivity to treatment whereas the patient tumor showed progression under the same treatment. These different behaviors can be observed in PDX models developed from multiple metastases of a same patient and may reflect different mechanisms of resistance. Most interestingly, PDX models obtained from different metastatic lesions of a same patient can recapitulate the different behavior observed in this patient. This behavior is translated by either tumor progression in one PDX model and/or stabilization under treatment in another. These paired models greatly facilitate the identification of relevant mechanisms of drug resistance.We have now completed the development of a panel of 25 PDX models of various indications and exposed to a variety of last generation targeted therapies. We will discuss relevant examples of results that can be generated from this panel, with particular focus on the molecular features of models with acquired or intrinsic resistance to treatment and of paired models with different drug sensitivity. These data highlight the unique potential of the MATCH-R preclinical platform to identify resistance mechanisms and develop next generation therapeutic strategies. Citation Format: Olivier Deas, Emilie Dassé, Laura Brulle-Soumare, Katell Mevel, Ludovic Bigot, Yohann Loriot, Fabrice André, Jean-Charles Soria, Benjamin Besse, Enora Le Ven, Stefano Cairo, Luc Friboulet, Jean-Gabriel Judde. Identification of the mechanisms of resistance to targeted therapies in advanced solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3016.