{"entity":{"id":"paper-engelman-met-amplification-gefitinib-resistance-science-2007","kind":"paper","name":"MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling","aka":[],"tldr":"Some lung cancers escape a targeted pill without changing the target at all: they simply make many extra copies of a second receptor that switches the same growth signal back on.","summary":"A gefitinib-sensitive lung cancer cell line that developed resistance was found to carry focal amplification of the MET proto-oncogene, and inhibiting MET signalling restored sensitivity. MET amplification was detected in 4 of 18 lung cancer specimens, 22%, that had developed resistance to gefitinib or erlotinib. Amplification of MET causes resistance by driving ERBB3-dependent activation of PI3K, a pathway previously thought to be specific to the EGFR and ERBB receptor family, so MET amplification may promote drug resistance in other ERBB-driven cancers as well.","asOf":"2026-09-25","links":[{"label":"Engelman et al., Science 2007: MET amplification causes gefitinib resistance by activating ERBB3 signalling","url":"https://doi.org/10.1126/science.1141478"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/17463250/"}],"tags":[],"related":["met-amplification-readout"],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["met","egfr"],"drugs":["gefitinib","erlotinib"],"companies":[],"institutions":["mgh","dana-farber"],"pathways":["rtk-activation","pi3k-akt-mtor","resistance-routes-map"],"terms":["met-amplification","resistance","gene-amplification"],"trials":[],"people":["pasi-janne"],"bottlenecks":[],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2007,"doi":"10.1126/science.1141478","pmid":"17463250","authors":"Engelman JA, Zejnullahu K, Mitsudomi T, et al.","paperType":"basic","findings":["MET amplification in 4 of 18 specimens with acquired resistance to an EGFR inhibitor, 22%.","Resistance is driven through ERBB3-dependent PI3K activation, not through EGFR.","Inhibiting MET restored sensitivity to gefitinib in the resistant line."],"whatItMeans":"It defined bypass resistance as a category and set the treatment rule that follows from it: keep blocking the original target and add an inhibitor of the bypass, which is the logic of every EGFR plus MET combination since.","caveats":["Eighteen specimens, so the 22% figure is imprecise and larger series have found lower rates at first-generation resistance.","Copy-number thresholds for calling amplification vary.","Cell line work leads the clinical evidence."],"changedPractice":true,"participants":18},"route":"/key-papers/paper-engelman-met-amplification-gefitinib-resistance-science-2007/","neighbours":{"biomarker":[{"id":"met-amplification-readout","kind":"biomarker","name":"MET amplification (gene copy number)","route":"/biomarkers/met-amplification-readout/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"}],"drug":[{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"},{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"}],"pathway":[{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"gene-amplification","kind":"term","name":"Gene amplification and copy-number change","route":"/terms/gene-amplification/"},{"id":"met-amplification","kind":"term","name":"MET amplification (bypass resistance)","route":"/terms/met-amplification/"}],"person":[{"id":"pasi-janne","kind":"person","name":"Pasi A. Jänne","route":"/people/pasi-janne/"}],"journal":[{"id":"science","kind":"journal","name":"Science","route":"/journals/science/"}]}}