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Mutant selective epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first‐generation EGFR‐TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX‐2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX‐2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by  MET  amplification. One was bypass signaling by  MET  amplification in addition to T790M, which was inhibited by the combination of CNX‐2006 and MET‐TKI. Another was loss of amplified  EGFR  mutant allele including T790M while acquiring  MET  amplification. Interestingly, MET‐TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an “oncogene swap.” Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the  EGFR  mutation was lost and a  MET  gene copy was gained. In conclusion, an “oncogene swap” from  EGFR  to  MET  is a novel resistant mechanism to the EGFR‐TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene.

Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor‐tyrosine kinase inhibitor in lung cancer