T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, [ 1 ] affecting the ATP binding pocket of the EGFR kinase domain.

The T790M mutation is most commonly found in cases of non-small-cell lung cancer (NSCLC) carrying a TKI-sensitive EGFR mutation (most frequently an in-frame deletion in exon 19 or an L858R point mutation in exon 21) that have developed resistance after TKI treatment.

2010年12月2日 · Subsequent studies found that a secondary mutation in the EGFR gene (T790M mutation) and amplification of the MET proto-oncogene could be the main resistance mechanisms involved. The current review is focused on T790M, which is thought to cause steric hindrance and impair the binding of gefitinib/erlotinib.

EGFR T790M is a predictive biomarker for use of osimertinib, afatinib, dacomitinib, erlotinib, gefitinib, capmatinib, cetuximab, crizotinib, and pembrolizumab in patients. Of the therapies with EGFR T790M as a predictive biomarker, 2 are FDA-approved and 8 have NCCN guidelines in at least one clinical setting.

The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors.

Several second-generation EGFR-TKIs are currently being developed to overcome the acquired resistance caused by the T790M mutation. MET (met proto-oncogene) amplification or activation of IGF1R are reported as alternative mechanisms for acquired resistance to EGFR-TKIs.

The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs.

2017年2月16日 · In this trial, we found that patients with T790M-positive advanced non–small-cell lung cancer who received osimertinib had better response rates and a longer duration of progression-free ...

2012年1月3日 · T790M was an independent predictor of decreased progression-free survival (PFS) in patients with NSCLC who received TKI treatment (P < .05, multivariate Cox regression).

2019年11月21日 · Osimertinib is a third-generation, irreversible, oral EGFR-TKI that selectively inhibits both EGFR-TKI–sensitizing and EGFR p.Thr790Met (T790M) resistance mutations and has shown efficacy in...