title: Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer.
abstract: 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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231-1000, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Jordy
authors.initials: J
authors.lastname: Coffa
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.forename: Peter
authors.initials: P
authors.lastname: Kulesza
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viqueira
authors.forename: Jenna
authors.initials: J
authors.lastname: Wheelhouse
authors.forename: Begoña
authors.initials: B
authors.lastname: Diosdado
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab