Metamplification induces an aggressive phenotype in EGFR tyrosine kinase inhibitors resistant non-small-cell lung cancer

Abstract

Introduction: Treatment of Non-Small-Cell Lung Cancer (NSCLC) harboring an Epidermal Growth Factor Receptor (EGFR) mutation relies on EGFR tyrosine kinase inhibitors (TKI). However all patients treated with EGFR TKI eventually present tumor progression, because of mechanisms of resistance such as amplification of the met receptor gene. There is currently no data on cellular phenotypic changes of tumor cells induced by met amplification in this context. Objective: to determine whether met amplification triggers a more aggressive tumor phenotype in TKI resistant EGFR-mutated NSCLC. Methods: The proliferation and migration capacities were studied in HCC827 cell line, derived from a mutated EGFR NSCLC, and his daughter cell line HCC827 GR6 which is resistant to EGFR TKI through amplification of the met gene. Tumor growth of both strains was analyzed in a mouse model of ectopic xenograft. Results: in vitro, we found a similar proliferation in the two cell lines and a significant increase in migration and anchorage-independant growth in the met amplified cell line. Treatment with PHA-665752, a MET TKI, significantly reduced the migration advantage of met amplified cells. In vivo, we observed a significant increase in tumor growth with the met amplified cell line. In vivo results regarding the metastatic potential of the two cell lines and the impact of EGFR and MET TKI will be presented during the meeting. Conclusion: met amplification confers an aggressive phenotype to TKI resistant EGFR-mutated NSCLC. These results pave the way for an early use of MET inhibitors in association with EGFR TKI in order to prevent emergence of an aggressive tumor clone.