{"entity":{"id":"paper-pao-egfr-t790m-acquired-resistance-plos-med-2005","kind":"paper","name":"Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain","aka":[],"tldr":"Published within weeks of the single-patient report, this study found the same resistance change in several more patients and showed it was not there before treatment, so the drug had selected it.","summary":"In two of five patients with acquired resistance to gefitinib or erlotinib, the progressing tumours contained, in addition to a primary drug-sensitive EGFR mutation, a secondary mutation in exon 20 leading to substitution of methionine for threonine at position 790. Tumour cells from a sixth patient with a drug-sensitive mutation whose tumour progressed on adjuvant gefitinib after complete resection also contained T790M. The mutation was not detected in untreated tumour samples. No tumour with acquired resistance carried a KRAS mutation. Biochemical analyses of transfected cells and growth inhibition studies in lung cancer cell lines showed that T790M confers resistance to EGFR mutants otherwise sensitive to either drug. An analogous mutation had been observed in another kinase with acquired resistance to imatinib.","asOf":"2026-09-25","links":[{"label":"Pao et al., PLoS Med 2005: a second EGFR kinase-domain mutation in lung adenocarcinomas with acquired resistance to gefitinib or erlotinib","url":"https://doi.org/10.1371/journal.pmed.0020073"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15737014/"}],"tags":[],"related":["egfr-t790m"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["egfr","kras"],"drugs":["gefitinib","erlotinib"],"companies":[],"institutions":["mskcc"],"pathways":["rtk-activation","resistance-routes-map","clonal-evolution"],"terms":["resistance","egfr-mutation-subtypes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["plos-medicine"],"dependsOn":[],"notes":[],"journal":"PLOS Medicine","year":2005,"doi":"10.1371/journal.pmed.0020073","pmid":"15737014","authors":"Pao W, Miller VA, Politi KA, et al.","paperType":"translational","findings":["T790M found in resistant tumours from three of six patients and absent from untreated samples.","No KRAS mutations in the resistant tumours, distinguishing acquired from primary resistance.","Cell line work confirmed the mutation confers resistance.","The gatekeeper position parallels imatinib resistance in another kinase."],"whatItMeans":"It generalised the single-patient finding and made the point that drug-resistant subclones are selected by treatment rather than created by it, which is the model the whole field now works with.","caveats":["Six patients.","Detection methods of the time could not exclude pre-existing low-frequency T790M.","Only tumours that could be rebiopsied were studied, which selects for accessible disease."],"changedPractice":true,"participants":6},"route":"/key-papers/paper-pao-egfr-t790m-acquired-resistance-plos-med-2005/","neighbours":{"biomarker":[{"id":"egfr-t790m","kind":"biomarker","name":"EGFR T790M","route":"/biomarkers/egfr-t790m/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"},{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"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":"egfr-mutation-subtypes","kind":"term","name":"EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)","route":"/terms/egfr-mutation-subtypes/"}],"journal":[{"id":"plos-medicine","kind":"journal","name":"PLOS Medicine","route":"/journals/plos-medicine/"}]}}