Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer

Antonio Jimeno, Aik-Choon Tan, Jordy Coffa, N. V. Rajeshkumar, Peter Kulesza, Belen Rubio-Viqueira, Jenna Wheelhouse, Begoña Diosdado, Wells A. Messersmith, Christine Iacobuzio-Donahue, Anirban Maitra, Marileila Varella-Garcia, Fred R. Hirsch, Gerrit A. Meijer, Manuel Hidalgo

Research output: Contribution to journalArticle

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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). Analys is 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. Coordinate d 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.

Original languageEnglish
Pages (from-to)2841-2849
Number of pages9
JournalCancer Research
Volume68
Issue number8
DOIs
Publication statusPublished - 2008 Apr 15
Externally publishedYes

Fingerprint

erbB-1 Genes
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
gemcitabine
Neoplasms
Gene Components
Systems Biology
Gene Amplification
Multiplex Polymerase Chain Reaction
Mitogen-Activated Protein Kinase Kinases
Gene Expression Profiling
Fluorescence In Situ Hybridization

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer. / Jimeno, Antonio; Tan, Aik-Choon; Coffa, Jordy; Rajeshkumar, N. V.; Kulesza, Peter; Rubio-Viqueira, Belen; Wheelhouse, Jenna; Diosdado, Begoña; Messersmith, Wells A.; Iacobuzio-Donahue, Christine; Maitra, Anirban; Varella-Garcia, Marileila; Hirsch, Fred R.; Meijer, Gerrit A.; Hidalgo, Manuel.

In: Cancer Research, Vol. 68, No. 8, 15.04.2008, p. 2841-2849.

Research output: Contribution to journalArticle

Jimeno, A, Tan, A-C, Coffa, J, Rajeshkumar, NV, Kulesza, P, Rubio-Viqueira, B, Wheelhouse, J, Diosdado, B, Messersmith, WA, Iacobuzio-Donahue, C, Maitra, A, Varella-Garcia, M, Hirsch, FR, Meijer, GA & Hidalgo, M 2008, 'Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer', Cancer Research, vol. 68, no. 8, pp. 2841-2849. https://doi.org/10.1158/0008-5472.CAN-07-5200
Jimeno, Antonio ; Tan, Aik-Choon ; Coffa, Jordy ; Rajeshkumar, N. V. ; Kulesza, Peter ; Rubio-Viqueira, Belen ; Wheelhouse, Jenna ; Diosdado, Begoña ; Messersmith, Wells A. ; Iacobuzio-Donahue, Christine ; Maitra, Anirban ; Varella-Garcia, Marileila ; Hirsch, Fred R. ; Meijer, Gerrit A. ; Hidalgo, Manuel. / Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer. In: Cancer Research. 2008 ; Vol. 68, No. 8. pp. 2841-2849.
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