Overall, these findings strongly suggest that when a bona fide, full mesenchymal phenotype develops upon chronic exposure of intrinsically aggressive variant 3a/b-harboring ALK-rearranged NSCLC cells to a first-generation ALK–TKI (crizotinib), those cells are no longer responsive to second and third-generation ALK–TKIs. The gene discussed is ALK; the disease is non-small cell lung carcinoma.