The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

By C. Yun, Kristen E. Mengwasser, A. Toms, M. S. Woo, H. Greulich, Kwok-kin Wong, Matthew Meyerson, M. Eck. Proceedings of the National Academy of Sciences of the United States of America, 2008

2,013 citations recorded by the source corpus.

Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the “gatekeeper” residue, an important determinant of inhibitor specificity in the ATP binding pocket. 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. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/e440d86520e441cf0e0280daad18e9de55da9c5f

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Citations in the corpus

Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC (2010, background): “To date, resistance mechanisms have predominately involved secondary genomic alterations in the target kinase that alter either the physical (such as steric hindrance) or biochemical (change in ATP affinity) properties of the receptor and result in drug resistance (Gorre et al., 2001; Shah et al., 2”
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways (2017, background): “Third generation EGFR TKIs are being developed to target T790M, including Brigatinib, HM61713, osimertinib, and rociletinib [391].”
The resurgence of covalent drugs (2011, background): “An irreversible mechanism of action also helps to mitigate against competition by high intracellular concentrations of AT”
Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation (2010, neutral): “Median time from progression to new metastatic organ involvement, months* 14 (8-18) 4 (1-9) 0.”
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “Threonine is replaced by methionine, altering the configuration of the kinase domain and enhancing its affinity (over wild-type) for ATP, with corresponding decreased affinity for first-generation reversible TKIs (81).”
Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls (2015, background): “Examples of covalent inhibitors including their protein target(s) with active-site nucleophile: (A) aspirin; (B) neratinib; (C) rivastigmine; (D) Crystal structure of EGFR kinase domain in complex with neratinib, showing the covalent bond between the receptor and the ligand [27].”
Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer (2012, neutral): “involves a change in the target of the drug, specifically a second EGFR mutation, T790M, that alters the binding kinetics of the reversible TKIs to the target molecule (10).”
The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review) (2017, neutral): “…target) occurs when the drug target protein has changed due to steric hindrance to inhibitor binding (150), altered active site topography (151), disruption of favorable inhibitor interactions (152), altered protein dynamics (153), increased oncogenicity (151), and alteration of ATP affinity (154).”
ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, background): “Although HER3 can bind ATP and catalyze autophosphorylation, it has a weak kinase activity compared to that of its ERBB coreceptors (Shi et al., 2010).”