Abstract
Simple SummaryThe use of targeted therapy has changed the clinical management of lung cancer patients, increasing both their life quality and expectancy. Conversely, the appearance of resistance occurs in almost all patients receiving this therapy. In this regard, new strategies combining different therapies could delay or even eliminate the appearance of resistance. However, in order to develop new therapeutic treatments, we need preclinical mouse models that recapitulate human disease. In the present study, we developed a new state-of-the-art mouse model that summarizes all features occurring in EGFR-mutated patients that relapse after osimertinib after acquisition of MET amplification.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 EGFRT790M/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 EGFRT790M/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.
Highlights
epidermal growth factor receptor (EGFR)-activating mutations, such as exon 19 deletion or the L858R mutation in exon 21, occur in 10–15% of patients with non-small cell lung cancer
In the FLAURA phase 3 clinical trial, progression-free survival and overall survival were longer with osimertinib than with first-generation tyrosine kinase inhibitors (TKIs) and, in many countries, osimertinib has become the first-line standard of care for patients with EGFR-mutated non-small cell lung cancer (NSCLC) [3]
To develop a mouse model that could recapitulate osimertinib resistance caused by MET amplification in patients with EGFR-mutated lung cancer, we took advantage of a mouse strain in which liver carcinoma develops upon induction of human WT MET expression in the liver [7]
Summary
EGFR-activating mutations, such as exon 19 deletion or the L858R mutation in exon 21, occur in 10–15% of patients with non-small cell lung cancer. For these patients, targeted therapy is proposed as first-line treatment because it provides a clear advantage compared to standard chemotherapy. In the FLAURA phase 3 clinical trial, progression-free survival and overall survival were longer with osimertinib than with first-generation TKIs and, in many countries, osimertinib has become the first-line standard of care for patients with EGFR-mutated non-small cell lung cancer (NSCLC) [3]. A very recent phase 1b clinical trial showed a therapeutic benefit of the combination of osimertinib and the MET inhibitor savolitinib in this patient subtype [5]. Our new compound mouse strain will pave the way to in vivo preclinical studies to test new therapeutic options in this specific genetic context with important clinical implications
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