The objective of this work was twofold: On the one hand, to determine if the mere process of EMT is sufficient to foster the resistance of lung cancer cells to various generations of ALK tyrosine kinase inhibitors (TKIs); on the other hand, to test the capacity of the natural compound silibinin to re-sensitize lung cancer cells that gained a mesenchymal phenotype to the anti-tumor activity of ALK–TKIs. Here, ALK is linked to lung cancer.