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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.
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.
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.
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 T790M, Gefitinib, Erlotinib, Resistance routes: how a blocked pathway comes back.
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 T790M, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease.
Shares EGFR T790M, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation.
Shares Gefitinib, Erlotinib, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares EGFR T790M, EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M), Gefitinib, Resistance routes: how a blocked pathway comes back.
Shares EGFR T790M, Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease, Drug resistance (primary and acquired).