EGFR and lung cancer: As evidenced in lung cancer studies, secondary METamp is found in EGFR T790M tumors that are resistant to the EGFR TKIs erlotinib or gefitinib [44], demonstrating that long-term treatment with TKI alone may allow NHEJ-mediated chromosomal rearrangement, leading to acquired resistance through alternative pathway activation (Fig. 6a).