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Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer

¹ Sidney Kimmel Comprehensive Cancer Center and ² Institute for Computational Medicine at Johns Hopkins University, Baltimore, Maryland; ³ Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; ⁴ University of Colorado Cancer Center, Aurora, Colorado; and ⁵ Centro Intregral Oncologico Clara Campal, Madrid, Spain

Requests for reprints: Manuel Hidalgo, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 1650 Orleans Street, Room 1M88, Baltimore, MD 21231-1000. Phone: 410-502-3850; Fax: 410-614-9006; E-mail: mhidalg1{at}jhmi.edu.

Key Words: EGFR • pancreatic cancer • pathway addiction

The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development. [Cancer Res 2008;68(8):2841–9]