{"entity":{"id":"egfr-c797s","kind":"biomarker","name":"EGFR C797S (and its phase with T790M)","aka":["C797S","EGFR C797S","C797S in cis","C797S in trans","Cys797Ser"],"tldr":"A change in the EGFR protein that removes the anchor point the newest lung cancer pills grip. Whether it can be worked around depends on whether it sits on the same copy of the gene as the earlier resistance change or on the other copy.","summary":"Osimertinib and the other third-generation EGFR inhibitors bind covalently to the cysteine at position 797. Substituting serine for that cysteine removes the covalent bond and confers resistance, and it was first identified in plasma from patients progressing on osimertinib (Thress 2015). It was found in 9 of 41 tumours sequenced at osimertinib resistance, 22%, and occurred in the third of patients who retained T790M (Oxnard 2018); cBioPortal records it in 19 of 2,653 lung adenocarcinoma samples in luad_mskcc_2023_met_organotropism and 20 of 2,621 in nsclc_ctdx_msk_2022, cohorts made largely of treated patients resequenced at progression. The result that matters is not the presence of C797S but its allelic phase relative to T790M: in trans, a first-generation and a third-generation inhibitor together can cover both alleles; in cis, neither can, and the options are a fourth-generation or allosteric inhibitor in a trial, an EGFR-MET bispecific antibody, or chemotherapy. Phase can be called from sequencing reads when both variants fall within one read pair, and plasma assays report it inconsistently.","asOf":"2026-09-25","links":[{"label":"Thress et al., Nat Med 2015: acquired EGFR C797S mediates resistance to osimertinib in T790M-positive lung cancer","url":"https://doi.org/10.1038/nm.3854"},{"label":"Oxnard et al., JAMA Oncol 2018: resistance mechanisms after osimertinib in T790M-positive lung cancer (143 and 110 patients)","url":"https://doi.org/10.1001/jamaoncol.2018.2969"},{"label":"cBioPortal study luad_mskcc_2023_met_organotropism (MSK, Cancer Cell 2023; 2,653 MSK-IMPACT lung adenocarcinoma samples, 2,422 with copy number and structural variants)","url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism"}],"tags":["biomarker","resistance"],"related":["egfr-t790m","egfr-exon-19-deletion","egfr-l858r"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["egfr"],"drugs":[],"companies":[],"institutions":[],"pathways":["resistance-routes-map","rtk-activation"],"terms":["resistance","egfr-mutation-subtypes","ctdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-thress-nat-med","paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018"],"journals":[],"dependsOn":[],"notes":[],"target":"egfr","measurement":"sequencing-variant","scoringRule":{"text":"Presence of the EGFR p.Cys797Ser substitution on tumour or plasma sequencing, reported together with T790M status and, where the reads allow it, with the allelic phase of the two variants.","quote":"acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M","source":"https://doi.org/10.1038/nm.3854","sourceLabel":"Thress et al., Nature Medicine 2015"},"thresholds":[],"definedBy":{"label":"Oxnard et al., JAMA Oncology 2018: resistance mechanisms after osimertinib in T790M-positive lung cancer","url":"https://doi.org/10.1001/jamaoncol.2018.2969"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result explains why a targeted tablet has stopped working. It does not close off treatment: which options remain depends on a further detail of the sequencing report, and a specialist centre or a trial is often the next step."},"route":"/biomarkers/egfr-c797s/","neighbours":{"biomarker":[{"id":"egfr-exon-19-deletion","kind":"biomarker","name":"EGFR exon 19 deletion","route":"/biomarkers/egfr-exon-19-deletion/"},{"id":"egfr-l858r","kind":"biomarker","name":"EGFR L858R","route":"/biomarkers/egfr-l858r/"},{"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/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"pathway":[{"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":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"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/"}],"paper":[{"id":"paper-thress-nat-med","kind":"paper","name":"Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M","route":"/key-papers/paper-thress-nat-med/"},{"id":"paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018","kind":"paper","name":"Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib","route":"/key-papers/paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018/"}]}}