Resistance mechanisms to EGFR-TKI can be classified in three main groups [34]: (1) Target alterations: secondary mutations on EGFR or EGFR amplifications [35]; (2) Activation of bypass signalling pathways, such as PI3K/AKT, MAP kinase pathway, IGFR1, AXL, IGFR1/KDM5A, or amplifications of MET, HER2 or SMO [36,37,38,39,40,41]; and (3) Transformation of the cellular phenotype by epithelial to mesenchymal transition (EMT) or histological transformation to small-cell lung cancer (SCLC) [22,42,43,44]. Here, KDM5A is linked to small cell lung carcinoma.