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


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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    • "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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