A novel mesenchymal epithelial transition (MET) inhibitor, CB538, relieves acquired resistance in EGFR-mutated MET-amplified non-small cell lung cancer.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is the first-line standard therapy for metastatic EGFR-mutated non-small cell lung cancer (NSCLC). Although osimertinib is effective, it's durable response is invariably limited by the emergence of acquired resistance. Mesenchymal epithelial transition (MET) amplification is a frequent mechanism in patients with EGFR-mutated NSCLC who are resistant to EGFR-TKIs. Consequently, combined treatment with EGFR-TKIs and MET-TKIs has been explored as a strategy for overcoming this resistance. The current study aimed to explore the single and combination inhibition effect of CB538, a novel MET inhibitor in MET-activated, EGFR-mutant NSCLC cells. METHODS: The cellular inhibitory effects of single and co-treatment of CB538 with EGFR-TKIs were evaluated in the established EGFR-TKI-resistant cells [PC9/ER (erlotinib resistance), HCC827/OR (osimertinib resistance)]. The preclinical activities of CB538 were investigated by evaluating in vitro kinase activity, cell growth, and Western blotting of phosphorylated MET and downstream signaling molecules in MET-activated, EGFR-TKI-resistant cells. Cell viability was examined by MTT and colony formation. The inhibition of migration was determined by wound-healing assay. A xenograft tumor model was employed to investigate in vivo HCC827/OR cell growth in BALB/c nude mice. RESULTS: We confirmed that activated MET/Axl signaling pathways and EMT-related proteins were inhibited by CB538 in established EGFR-TKI-resistant NSCLC cells. CB538, a novel c-MET inhibitor, decreased the growth, migration, and invasive properties of these EGFR-TKI-resistant NSCLC cells. CB538 also inhibited tumor growth and expression of activated proteins (MET and Axl) in in vivo HCC827/OR xenograft model. CONCLUSIONS: Additional treatment with CB538 enhanced sensitivity to EGFR-TKIs in two EGFR-TKI-resistant NSCLC cells by inhibiting EGFR/MET/Axl pathway axis. Overall, the treatment effects of CB538 were confirmed to relieve EGFR-TKI-driven resistance in EGFR-mutant NSCLC cells.