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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.
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.
In plain words · A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.
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.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
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.
“acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M”
Thress et al., Nature Medicine 2015No approval uses this readout as a threshold. It is defined by Oxnard et al., JAMA Oncology 2018: resistance mechanisms after osimertinib in T790M-positive lung cancer.
Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.
It changed how resistance is investigated: the first question at progression on osimertinib is whether T790M is still there, because losing it means the tumour is no longer EGFR-driven in the growing compartment and another EGFR inhibitor will not help.
One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation, Comprehensive genomic profiling and the tags biomarker, resistance.
Shares Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, EGFR T790M, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares Circulating tumour DNA (ctDNA) and the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares EGFR T790M, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares EGFR L858R, EGFR T790M, EGFR exon 19 deletion, Circulating tumour DNA (ctDNA).
Shares EGFR exon 19 deletion, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), EGFR, Non-small-cell lung cancer and the tag biomarker.
Shares Circulating tumour DNA (ctDNA), Liquid biopsy (ctDNA) and the tag biomarker.