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Cellular sensitivity to EGF receptor inhibitors

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EGFR Signaling Networks in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The EGFR pathway is a critical signaling pathway regulation cell proliferation and survival. As such, it is frequently deregulated in cancer through over expression of both EGF family ligands and receptors and by mutation of critical components within the pathway. These characteristics have made this signaling axis an attractive target for the development of molecularly targeted therapies in the treatment of cancer. To date there are numerous small molecule inhibitors and antibodies, either already in clinical use or in late stage clinical trials, that specifically target EGFR. These inhibitors have achieved great success in treating cancer patients and have generated a large amount of interest in identifying molecular markers that predict clinical benefit and mechanisms of resistance to such treatments. The first major breakthrough in this line of research was the identification of mutations in the EGFR kinase domain, which rendered the receptor hypersensitive to the actions of small molecule kinase inhibitors. However, the mutation rate was insufficient to explain the overall clinical benefit observed with these inhibitors, suggesting patients with wild-type EGFR also received some benefit. Subsequently, numerous efforts have been made to identify biomarkers of response and resistance other than EGFR mutational status.

Here we will summarize the current literature describing attempts to identify such markers, with particular emphasis on markers of sensitivity and resistance to small molecule EGFR tyrosine kinase inhibitors (TKIs). These approaches have encompassed the analysis of expression levels, both at the protein and genomic level, of EGFR and the closely related family members HER2 and HER3 and the analysis of the mutational status of downstream components of the EGFR pathway. In addition, we will highlight the role of the epithelial to mesenchymal transition (EMT) in sensitivity to small molecule EGFR TKIs and finally the potential role of alternative signaling cascades as a mode of cellular resistance to EGFR inhibition.

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Authors and Affiliations

  1. Translational Research, OSI Pharmaceuticals Inc., 1 Bioscience Park Dr, Farmingdale, NY, 11735, USA

    Stuart Thomson PhD

  2. Translational Research, OSI Pharmaceuticals Inc., 1 Bioscience Park Dr, Farmingdale, NY, 11735, USA

    John D. Haley PhD

  3. Genentech Inc., 1 DNA Way, MS. 93B, South San Francisco, CA, 94080

    Robert Yauch PhD

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  1. Stuart Thomson PhD
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  2. John D. Haley PhD
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Editors and Affiliations

  1. OSI Pharmaceuticals, Inc., Bioscience Park Drive 1, Farmingdale, 11735, U.S.A.

    John D. Haley

  2. Dept. Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, United Kingdom

    William John Gullick

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Thomson, S., Haley, J.D., Yauch, R. (2008). Cellular sensitivity to EGF receptor inhibitors. In: Haley, J., Gullick, W. (eds) EGFR Signaling Networks in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-356-1_22

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  • DOI: https://doi.org/10.1007/978-1-59745-356-1_22

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