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PTEN-Mediated Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors

Author's Affiliations: Departments of ¹ Molecular and Medical Pharmacology, ² Neurology, and ³ Pathology and ⁴ Henry E. Singleton Brain Tumor Program, David Geffen School of Medicine, University of California, Los Angeles, California

Requests for reprints: Paul S. Mischel, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732. Phone: 310-794-5223; Fax: 310-206-0657; E-mail: pmischel{at}mednet.ucla.edu.

Abstract

Molecularly targeted therapies are transforming the treatment of cancer. Elucidating the dynamic signaling networks that underlie sensitivity and resistance to these inhibitors is critical for successful clinical application. There is considerable evidence to suggest that constitutively activating mutations in kinases that regulate cellular growth may result in tumor cell "addiction" and favorable response to targeted inhibition. However, there is emerging evidence to suggest that clinical response may also be determined by other changes in the molecular circuitry of cancer cells, such as loss of key tumor-suppressor proteins. Here, we will discuss resistance to epidermal growth factor receptor tyrosine kinase inhibitors in glioblastoma patients that is mediated by loss of the PTEN tumor-suppressor protein.

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