We show that the acquisition of a mesenchymal phenotype by ALK-rearranged NSCLC cells following chronic exposure to crizotinib or to TGFβ stimulation increases resistance to the second-generation ALK–TKI brigatinib and promotes full refractoriness to the third-generation ALK–TKI lorlatinib. This evidence concerns the gene ALK and non-small cell lung carcinoma.