ClinVar Genomic variation as it relates to human health

In a tumor with the 2240del18 mutation in the EGFR gene (131550.0001) from a patient with nonsmall cell lung cancer (211980) who showed responsiveness to gefitinib with complete remission over a 2-year period, Kobayashi et al. (2005) identified the development of a second mutation in EGFR, thr790 to met (T790M), responsible for secondary resistance to gefitinib. Kobayashi et al. (2005) noted that one of the most common imatinib resistance mutations in ABL1/BCR in leukemia replaces threonine at position 315 (the amino acid structurally corresponding to T790 of EGFR) with isoleucine in the ABL tyrosine kinase domain (thr315 to ile; 189980.0001). The T315I substitution leads to a structural change very similar to that observed with T790M (Gorre et al., 2001). In 2 women with nonsmall cell lung cancer, Toyooka et al. (2005) identified 2 EGFR mutations, T790M and L858R (131550.0002), in resected tumor specimens taken before treatment with chemotherapy or radiation. Both patients later had recurrent disease and eventually died, suggesting that tumors with both these mutations are very aggressive. One patient was treated with gefitinib and had progression. Approximately 10% on of nonsmall cell lung cancers respond markedly to treatment with tyrosine kinase inhibitors that target EGFR. Responsive tumors are characteristically adenocarcinomas, often with bronchoalveolar (BAC) differentiation, and they are most common in nonsmokers, women, and Asians. Molecular analyses identified specific mutations in the kinase domain of EGFR in approximately 80% of responsive cases, e.g., an 18-bp deletion (131550.0001) and a missense mutation, L858R (131550.0002). These characteristic missense mutations and in-frame deletions affect residues of the ATP binding pocket, selectively enhancing ligand-dependent activation of the AKT/STAT survival pathways by the receptor. The T790M mutation was reported in cases of nonsmall cell lung cancers that recurred after initial response to tyrosine kinase inhibitors. Bell et al. (2005) studied a family of European descent in which multiple members developed the BAC subtype of nonsmall cell lung cancer. Six persons in 3 generations were affected. The cancer was found to be associated with germline transmission of the T790M mutation, suggesting that this mutation confers a growth advantage even in the absence of selective pressure of a tyrosine kinase inhibitor. Four of 6 tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M. These observations implicated altered EGFR signaling in genetic susceptibility to lung cancer. Yun et al. (2008) noted that thr790 is located at the entrance to a hydrophobic pocket in the back of the ATP binding cleft of EGFR. Substitution of thr790 with a bulky methionine has been postulated to cause resistance to reversible tyrosine kinase inhibitors through steric interference. However, Yun et al. (2008) used crystal structure analysis to show that certain irreversible inhibitors could still bind to the T790M-mutant EGFR, which is inconsistent with steric interference as a mechanism of drug resistance. Kinetic studies indicated that the L858R/T790M mutant receptor had increased ATP affinity compared to the L858R mutant alone, restoring ATP affinity close to that of wildtype. The T790M mutant alone and with L858R significantly increased kinase activity compared to wildtype. Yun et al. (2008) concluded that the T790M mutation will reduce the potency of any ATP-competitive kinase inhibitor, and that the primary mechanism of drug resistance conferred by T790M is increased ATP affinity. Zhou et al. (2009) identified a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wildtype EGFR, than quinazoline-based EGFR inhibitors in vitro. They were also affected in murine models of lung cancer driven by EGFR T790M. (less)