Differential Sensitivity of Glioma-versus Lung Cancer-Specific EGFR Mutations to EGFR Kinase Inhibitors

Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Discovery (Impact Factor: 19.45). 05/2012; 2(5):458-71. DOI: 10.1158/2159-8290.CD-11-0284
Source: PubMed

ABSTRACT Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.

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    • "EGFRvV; a deletion of exons 25–28) and mutations affecting the tyrosine kinase domain (mainly exon 19 and codon L858) [3] [4] [5]. These mutations result in a constitutively activated isoform of the protein and contribute to oncogenic transformation [5] [6] [7] [8]. "
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    ABSTRACT: Epidermal growth factor receptor (EGFR) is frequently mutated in various types of cancer. Although all oncogenic mutations are considered activating, different tumour types have different mutation spectra. It is possible that functional differences underlie this tumour-type specific mutation spectrum. We have determined whether specific mutations in EGFR (EGFR, EGFRvIII and EGFR-L858R) have differences in binding partners, differences in downstream pathway activation (gene expression and phosphoproteins), and have functional consequences on cellular growth and migration. Using biotin pulldown and subsequent mass spectrometry we were able to detect mutation specific binding partners for EGFR. Differential binding was confirmed using a proximity ligation assay and/or Western Blot for the dedicator of cytokinesis 4 (DOCK4), UDP-glucose glycoprotein glucosyltransferase 1 (UGGT1), MYC binding protein 2 (MYCBP2) and Smoothelin (SMTN). We also demonstrate that each mutation induces the expression of a specific set of genes, and that each mutation is associated with specific phosphorylation patterns. Finally, we demonstrate using stably expressing cell lines that EGFRvIII and EGFL858R display reduced growth and migration compared to EGFR wildtype expressing cells. Our results indicate that there are distinct functional differences between different EGFR mutations. The functional differences between different mutations argue for the development of mutation specific targeted therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 03/2015; 51(7). DOI:10.1016/j.ejca.2015.02.006 · 4.82 Impact Factor
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    • "Interestingly , the usefulness of certain irreversible EGFR inhibitors in EGFRvIII - positive GBM may obviate the need to combine c - MET and EGFR inhibitors ( Vivanco et al . , 2012 ) . Whether or not c - MET inhibitors are needed moving forward , SHP2 inhibitors might eventually offer an attractive alternative in the treatment of GBM where resistance to other inhibitors arises . Of course , our data support the potential usefulness of STAT3 inhibitors in treating GBM . STAT3 has previously been identified as a key"
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    ABSTRACT: Thousands of articles describing biomarkers predictive of treatment and prognostic of survival in cancer have been published, yet only a handful of biomarkers are currently used routinely in the clinic. Biomarkers need to be analytically standardized, validated, and clinically useful. This review will address the challenges and ways in which we can improve our discovery and translation of prospective biomarkers from the lab into validated diagnostic tests with a specific focus on patients diagnosed with glioblastoma and MGMT promoter methylation status. There has been long-held enthusiasm to use MGMT promoter methylation as a predictive biomarker for patients treated with the alkylating agent, temozolomide; however in the majority of centers around the world, this has not yet transpired.
    Frontiers in Neurology 01/2012; 3:188. DOI:10.3389/fneur.2012.00188
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