Generation and Characterization of a New Preclinical Mouse Model of EGFR-Driven Lung Cancer with MET-Induced Osimertinib Resistance

• Main Authors: Maicol Mancini, Quentin-Dominique Thomas, Sylvia Bourdel, Laura Papon, Emilie Bousquet, Prisca Jalta, Silvia La Monica, Camille Travert, Roberta Alfieri, Xavier Quantin, Marta Cañamero, Antonio Maraver
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Cancers
• Subjects: lung cancer; EGFR; MET; TKI; preclinical mouse models
• Online Access: https://www.mdpi.com/2072-6694/13/14/3441

Despite the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat advanced lung cancer harboring EGFR-activating mutations, the prognosis remains unfavorable because of intrinsic and/or acquired resistance. We generated a new state-of-the-art mouse strain harboring the human EGFR^T790M/L858R oncogene and MET overexpression (EGFR/MET strain) that mimics the MET amplification occurring in one out of five patients with EGFR-mutated lung cancer that relapsed after treatment with osimertinib, a third-generation anti-EGFR TKI. We found that survival was reduced in EGFR/MET mice compared with mice harboring only EGFR^T790M/L858R (EGFR strain). Moreover, EGFR/MET-driven lung tumors were resistant to osimertinib, recapitulating the phenotype observed in patients. Conversely, as also observed in patients, the crizotinib (anti-MET TKI) and osimertinib combination improved survival and reduced tumor burden in EGFR/MET mice, further validating the model’s value for preclinical studies. We also found that in EGFR/MET mice, MET overexpression negatively regulated EGFR activity through MIG6 induction, a compensatory mechanism that allows the coexistence of the two onco-genic events. Our data suggest that single EGFR or MET inhibition might not be a good therapeutic option for EGFR-mutated lung cancer with MET amplification, and that inhibition of both pathways should be the best clinical choice in these patients.