Abstract 4664: MatchR a preclinical platform of models resistant to innovative therapies
Authors: Bigot Ludovic , Nobre Catline , Facchinetti Francesco , Poiraudeau Loic , Braye Floriane , Sabio Jonathan , Menssouri Naoual , Deas Olivier , Nicotra Claudio , Ngo-Camus Maud , Tselikas Lambros , Scoazec Jean Yves , Fizazi Karim , Ponce Siantiago , Besse Benjamin , Friboulet Luc , Loriot Yohann 
Published: April 2023

Introduction: In the last 20 years, the advances in molecular oncology and cancer genetics allowed the identification of an increasing number of actionable oncogenic drivers and the development and clinical use of specific inhibitors. Despite these successes, it is now well established that tumour cells adapt and develop acquired resistance. It is crucial to understand these mechanisms of acquired resistance to develop overcoming therapeutic strategies. At Gustave Roussy, a prospective clinical trial MATCH-R (NCT02517892) is conducted to study the acquired resistance mechanisms and to find new therapeutic approaches for patients.. In parallel, of genetics analysis from patients biopsies, we develop Patient Derived Xenograft (PDX) to deepen our understanding of the resistance mechanism and to investigate new therapeutic approaches.

Material and Method: Fresh tumor biopsy specimens were obtained prospectively from patients through a prospective single-institution clinical trial (MATCH-R, NCT02517892). Patient derived xenografts (PDX) in NOD Scid Gamma (NSG) mice as well as patient derived organoids from PDX (PDXO) and Patient derived cell lines were developed and characterized. Extensive molecular profiling including whole exome sequencing (WES), RNA sequencing (RNAseq) and immunohistochemistry were performed on human samples; PDX; Patient derived cells lines and PDXO.

Results and Discussion: As of November 2022, 145 PDX models have been successfully obtained from 371 biopsies (global take rate of 39%). Our focus is the development of models from different cohorts: Androgen receptor inhibitors in castration-resistant prostate cancer, (18 PDX), ALK inhibitors in lung cancers (16 PDX including 3 post brigatinib, 7 post Lorlatinib and 6 Alectinib), EGFR inhibitors in lung cancers (33 PDX includind 24 post osimertinib), FGFR inhibitors in urothelial carcinoma and cholangiocarcinoma (29 PDX including 14 post erdafitinib, 4 post pemigatinib, 4 post futibatinib) and KRAS inhibitors in lung cancer and pancreatic cancers (20 PDX). The PDX models recapitulate the genetics, the phenotype and the pharmacology of the original biopsies. Novel mechanisms of resistance to tyrosine kinase inhibitors (TKI) in solid tumors were identified. Adaptive treatment with novel TKI or combinatorial strategies were evaluated to restore the sensitivity in PDX (readout: mean tumor growth). These results confirmed that PDX models are crucial to study the resistance mechanism and to develop new therapeutic strategies.

Conclusion: Overall, the MATCH-R study provides a unique preclinical platform to identify resistance mechanisms to innovative therapies and to develop next generation therapeutic strategies.

Citation Format: Ludovic Bigot, Catline Nobre, Francesco Facchinetti, Loic Poiraudeau, Floriane Braye, Jonathan Sabio, Naoual Menssouri, Olivier Deas, Claudio Nicotra, Maud Ngo-Camus, Lambros Tselikas, Jean Yves Scoazec, Karim Fizazi, Siantiago Ponce, Benjamin Besse, Luc Friboulet, Yohann Loriot. MatchR a preclinical platform of models resistant to innovative therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4664.