Mechanisms of acquired resistance to TKIs could be generally categorized into three classes: i) on-target mutations, like EGFR-T790M to first-/second-generation EGFR-TKIs; ii) off-target mutations: parallel, downstream or alternative pathways activation, like EGFR-independent resistant mechanisms caused by MET/HER2 amplification, HGF overexpression, etc.; iii) histological transformation into another type such as neuroendocrine or mesenchymal tumor [190]. The gene discussed is ERBB2; the disease is mesenchymal cell neoplasm.