Oncogenic mutant forms of EGFR: Lessons in signal transduction and targets for cancer therapy

The EGF-receptor is frequently mutated in a large variety of tumors. Here we review the most frequent mutations and conclude that they commonly enhance the intrinsic tyrosine kinase activity, or they represent loss-of-function of suppressive regulatory domains. Interestingly, the constitutive activi...

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Bibliographic Details
Published in:FEBS letters 2010-06, Vol.584 (12), p.2699-2706
Main Authors: Pines, Gur, Köstler, Wolfgang J., Yarden, Yosef
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - therapeutic use
EGFR
ErbB
Glioblastoma
HSP90 Heat-Shock Proteins - metabolism
Humans
Kinase
Lung cancer
Models, Biological
Mutation
Mutations
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - therapy
Oncogenes
Protein Kinase Inhibitors - therapeutic use
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - metabolism
Signal Transduction
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Summary:The EGF-receptor is frequently mutated in a large variety of tumors. Here we review the most frequent mutations and conclude that they commonly enhance the intrinsic tyrosine kinase activity, or they represent loss-of-function of suppressive regulatory domains. Interestingly, the constitutive activity of mutant receptors translates to downstream pathways, which are subtly different from those stimulated by the wild-type receptor. Cancer drugs intercepting EGFR signaling have already entered clinical application. Both kinase inhibitors specific to EGFR, and monoclonal antibodies to the receptor are described, along with experimental approaches targeting the HSP90 chaperone. Deeper understanding of signaling pathways downstream to mutant receptors will likely improve the outcome of current EGFR-targeted therapies, as well as help develop new drugs and combinations.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2010.04.019