Uncovering phenotypic heterogeneity of drug-tolerance in EGFR-mutated non-small cell lung cancer in vivo and in patients

Archive ouverte

Delahaye, Célia | Figarol, Sarah | Clermont, Estelle | Tosolini, Marie | Gence, Rémi | Asslan, Raghda | Pagano, Sandra | Fournié, Jean-Jacques | Pradines, Anne | Mazières, Julien | Calvayrac, Olivier | Favre, Gilles

Edité par CCSD -

International audience. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are effective therapies for advanced lung cancer patients bearing EGFR-activating mutations but are not curative due to the inevitable apparition of resistance. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant cells through non-genetic reprogramming. Here, we show that combination of EGFR-TKI with a farnesyl transferase inhibitor efficiently delays the relapse in EGFR-mutated patient-derived xenograft (PDX) models. We highlight phenotypic heterogeneity and different adaptive resistance mechanisms by single-cell RNA-sequencing from PDX samples after EGFR-TKI or combined treatments. We also propose to deepen our understanding of drug tolerance in patients by monitoring circulating tumour DNA and by performing phenotypic and molecular characterisation of circulating tumour cells in a cohort of EGFR-mutated adenocarcinoma patients treated with EGFR-TKI.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion