Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity

Yun, Cai‐Hong; Boggon, Titus J.; Li, Yiqun; Woo, Michele S.; Greulich, Heidi; Meyerson, Matthew; Eck, Michael J.

doi:10.1016/j.ccr.2006.12.017

Cited by 970 publications

(1,028 citation statements)

References 49 publications

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“…However, the combined mutant E709A +G719S was not investigated. In another study on in vitro kinase assay, the catalytic activity of G719S mutant was found to be 10-fold more active than WT EGFR (29). As amino acid glycine at position 719 is part of the highly conserved glycine-rich GXGXΦG motif (719GSGAFG724) present in the ATP-binding loop of protein kinases, it is suggested that it plays a crucial role in WT EGFR function (30).…”

Section: Discussionmentioning

confidence: 99%

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Tam

Leung

Tin

et al. 2009

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas, especially from nonsmoking women of Asian descent. We have previously shown EGFR mutations occur in >70% of lung adenocarcinoma from nonsmokers in our population with a complex mutational profile, including 13% of EGFR double mutations. In this study, we investigated the in vitro gefitinib response of four EGFR double mutants identified in untreated patients, including Q787R+L858R, E709A+G719C, T790M+L858R, and H870R+L858R. The phosphorylation profiles of EGFR and downstream effectors AKT, STAT3/5, and ERK1/2 were compared by immunoblot analyses among the single and double mutants transfected into H358 cells. Results showed that mutants responded to in vitro gefitinib treatment with different sensitivities. The G719C and L858R single mutants showed the highest gefitinib sensitivity compared with the corresponding coexisting single mutants E709A, Q787R, H870R, and T790M. The double mutants E709A+G719C, Q787R+L858R, and H870R+L858R showed attenuated responses to gefitinib in the EGFR and downstream effector phosphorylation profiles compared with G719C or L858R alone. T790M+L858R showed strong resistance to gefitinib. Clinically, the patient whose tumor contained H870R+L858R showed tumor stabilization by 250 mg oral gefitinib daily but cerebral metastasis developed 6 months later. Correlation with the in vitro phosphorylation profile of H870R +L858R suggested that treatment failure was probably due to inadequate suppression of EGFR signaling by the drug level attainable in the cerebrospinal fluid at the given oral dosage. Overall, the findings suggested that rare types of EGFR substitution mutations could confer relative gefitinib resistance when combined with the common activating mutants. [Mol Cancer Ther

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Section: Discussionmentioning

confidence: 99%

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Tam

Leung

Tin

et al. 2009

Molecular Cancer Therapeutics

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“…The kinase domain of EGFR generally exists in an auto-inhibited inactive conformation that adopts an active conformation by asymmetric contacts made during receptor dimerization [36]. EGFR kinase domain mutations in lung cancers destabilize the inactive conformation thereby favoring the active state [175]. Erlotinib and gefitinib bind the active conformation of the kinase domain and are effective in suppressing the activity of wild-type and certain mutant EGFRs [173,175].…”

Section: Targeted Therapymentioning

confidence: 99%

“…EGFR kinase domain mutations in lung cancers destabilize the inactive conformation thereby favoring the active state [175]. Erlotinib and gefitinib bind the active conformation of the kinase domain and are effective in suppressing the activity of wild-type and certain mutant EGFRs [173,175]. The binding characteristics of each TKI appear to vary with the specific EGFR mutation and in the future the choice of TKI may be tailored to the unique molecular features of individual tumors.…”

Section: Targeted Therapymentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

629

503

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The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

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“…28 The EGFR-TKD is likely to be the major site for TKI-resistance related mechanism to operate, because not only T790M mutation lies within this region, but in fact gefitinib and erlotinib, both EGFR specific TKIs used in this study, bind to the TKD on EGFR. 36,37 Gefitinib and erlotinib both exhibit much higher affinity to the active conformation of the EGFR-TKD over the inactive form. We propose that T790M mutation causes the EGFR-TKD to assume an intermediate conformation that favors the kinase activity but reduces affinity to the TKIs, giving the NSCLC cells resistance to the treatment.…”

Section: Discussionmentioning

confidence: 99%

Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

Zhen

Liu

et al. 2015

Cancer Biology & Therapy

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Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors; EPAS1, endothelial PAS domain-containing protein 1; HIF)-1a., hypoxia-inducible factorMutations in epidermal growth factor receptor (EGFR) rendering it constitutively active is one of the major causes for metastatic non-small-cell lung cancer (NSCLC), and EGFR-targeted therapies utilizing tyrosine kinase inhibitors (TKIs) are often used clinically as the first-line treatment. But approximately half of NSCLC patients develop resistance to these therapies, where the MET proto-oncogene is amplified by EGFR through the hypoxia-inducible factor (HIF)-1a. Here we report that endothelial PAS domain-containing protein 1 (EPAS1), with 48% sequence identity to HIF-1a, specifically binds to TKI-resistant T790M EGFR, but not to wild-type EGFR, in NSCLC cell lines. Expression of EPAS1 enhances amplification of MET when simultaneously expressed with T790M EGFR but not with wild-type EGFR, and this enhancement is independent of ligand binding domain of EGFR. MET amplification requires EPAS1, since EPAS1 knockdown reduced MET levels. When NSCLC cells expressing T790M EGFR were treated with TKIs, reduced EPAS1 levels significantly enhanced the drug effect, whereas over-expression of EPAS1 increased the drug resistant effect. This EPAS1-dependent TKI-resistance was abolished by knocking-down MET, suggesting that EPAS1 does not cause TKIresistance itself but functions to bridge EGFR and MET interactions. Our findings suggest that EPAS1 is a key factor in the EGFR-MET crosstalk in conferring TKI-resistance in NSCLC cases, and could be used as a potential therapeutic target in TKI-resistant NSCLC patients.

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Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity

Cited by 970 publications

References 49 publications

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

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