EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity

Medical University of Ohio at Toledo, Toledo, Ohio, United States
Cancer Research (Impact Factor: 9.33). 06/2007; 67(10):4665-70. DOI: 10.1158/0008-5472.CAN-07-0217
Source: PubMed


The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer.

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Available from: Susan M Pinney
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    • "Interestingly, the EGFR T790M mutation can also be found at low frequency (approximately 0.54% of never smokers with lung cancer) in the germ line of patients. The presence of a germline EGFR T790M mutation may be associated with increased risk of developing lung cancer [23–25]. In pretreated patients harboring a T790M mutation, low expression of BRCA1 mRNA is correlated with a prolonged progression-free survival to erlotinib treatment. "
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    ABSTRACT: The epidermal growth factor receptor (EGFR) is a well-characterized oncogene that is frequently activated by somatic kinase domain mutations in non-small cell lung cancer (NSCLC). EGFR TKIs are effective therapies for NSCLC patients whose tumors harbor an EGFR activating mutation. However, EGFR TKI treatment is not curative in patients because of both primary and secondary treatment resistance. Studies over the last decade have identified mechanisms that drive primary and secondary resistance to EGFR TKI treatment. The elucidation of mechanisms of resistance to EGFR TKI treatment provides a basis for the development of therapeutic strategies to overcome resistance and enhance outcomes in NSCLC patients. In this paper, we summarize the mechanisms of resistance to EGFR TKIs that have been identified to date and discusses potential therapeutic strategies to overcome EGFR TKI resistance in NSCLC patients.
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    • "Vikis et al. reported that standalone T790M mutations exhibit increased kinase activity. Furthermore, the human bronchial epithelial cell line that transfects T790M mutations has a higher growth advantage than wild-type cells, although not as high as that of deletion mutations [32]. Mulloy et al. showed that the T790M mutant exhibits tyrosine phosphorylation levels comparable to those of wild-type EGFR, whereas the T790M/L858R double mutant exhibits a substantial increase in phosphorylation compared with the L858R mutant alone [33]. "
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    ABSTRACT: Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.
    Full-text · Article · Jun 2011 · BioMed Research International
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    • "Bell et al [14] observed that this mutation seems to occur in cis with the p.L858R activating mutation. Kinase activity of EGFR p.T790M mutant has been reported as indistinguishable from wild-type EGFR [23,25], but Vikis et al [26] reported that p.T790M mutation alone causes increased phosphorylation levels. Godin-Heymann et al have shown that, although p.T790M mutation has a moderate effect on EGFR function, when combined with p.L858R or p.746_750del show a remarkable enhancement of EGFR activity [28]. "
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    ABSTRACT: A subset of lung cancer patients harbour EGFR somatic mutations in their tumours and are candidates for treatment with EGFR tyrosine kinase inhibitors. In a few cases EGFR mutations have also been found in the germ line, suggesting a role in lung carcinogenesis. Objetives of this study were: 1) To analyze the EGFR gene mutations in a population diagnosed with lung adenocarcinoma from Northern Spain. 2) To determine the frequency of a new germ-line mutation found in our laboratory as well as the frequency in our population of three other EGFR germ-line mutations detected by other authors. 3) To determine whether the novel mutation detected may have a functional effect on the EGFR protein. Tumour DNA samples were obtained from frozen or paraffin embedded tumour tissues. Samples of DNA from peripheral blood cells were obtained from 912 individuals with lung cancer recruited from the CAPUA study 12, 477 unrelated healthy donor individuals and 32 individuals with other types of cancer. EGFR gene exons 18 to 21 were studied by direct standard dideoxy sequencing. Specific mutations were determined either by direct sequencing or by specific RFLP analysis. Cell lines were transfected with EGFR-mutant plasmids and analysed by western blot with antibodies specific for total or phosphorylated-EGFR. We found EGFR mutation in 12 of the 71 tumour samples (17%). One tumour contained two mutations. One mutation (p.R776G) was present as a germ line. Using an RFLP analysis, this mutation was not found in 954 alleles from healthy individuals studied, concluding that it is not a polymorphism. The mutation was not found either in genomic DNA from 912 lung cancer patients. Three additional EGFR germ-line mutations that were already described were not found in any of the studied samples. These observations show that EGFR mutated alleles are rare in the population. In vitro studies revealed that tyrosine autophosphorylation is enhanced in p.R776G-mutant EGFR when compared with wild-type EGFR. This enhanced autophosphorylation in the absence of ligand may be associated with a proliferative advantage. Germ-line mutations in EGFR are rare but may contribute to oncogenesis.
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