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

TitleEvolution of MET and NRAS gene amplification as acquired resistance mechanisms in EGFR mutant NSCLC.
Publication TypeJournal Article
Year of Publication2021
AuthorsPeters TL, Patil T, Le AT, Davies KD, Brzeskiewicz PM, Nijmeh H, Bao L, Camidge DR, Aisner DL, Doebele RC
JournalNPJ Precis Oncol
Date Published2021 Oct 12

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.

Alternate JournalNPJ Precis Oncol
PubMed ID34642436
PubMed Central IDPMC8511249
Grant ListP30 CA046934 / CA / NCI NIH HHS / United States
P50 CA058187 / CA / NCI NIH HHS / United States
Related Faculty: 
Liming Bao, M.D., Ph.D.

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