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EGFR  mutant non-small cell lung cancer patients' disease demonstrates remarkable responses to EGFR-targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with  MET  gene amplification and then subsequently to a combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify  NRAS  gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed extracellular signal-related kinase activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR, and PI3K inhibitors. The combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to  NRAS  gene amplification.

Evolution of MET and NRAS gene amplification as acquired resistance mechanisms in EGFR mutant NSCLC