T790M
T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor. The mutation substitutes a threonine with a methionine at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinase domain. Threonine is a small polar amino acid; methionine is a larger nonpolar amino acid. Rather than directly blocking inhibitor binding to the active site, T790M increases the affinity for ATP so that the inhibitors are outcompeted; covalent inhibitors such as neratinib can overcome this resistance.Clinical
Over 50% of acquired resistance to EGFR tyrosine kinase inhibitors is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue, T790M.
In November 2015, the US FDA granted accelerated approval to osimertinib for the treatment of patients with metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer, as detected by an FDA-approved test, which progressed on or after EGFR TKI therapy.
