Epithelial membrane protein-1 is a biomarker of gefitinib resistance

Anjali Jain, Charles A. Tindell, Isett Laux, Jacob B. Hunter, John Curran, Anna Galkin, Daniel E. Afar, Nina Aronson, Steven Shak, Ronald B. Natale, David B. Agus

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59 Scopus citations

Abstract

We describe a molecular resistance biomarker to gefitinib, epithelial membrane protein-1 (EMP-1). Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on EGF receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples. We generated in vivo gefitinib-resistance models in an adenocarcinoma xenograft model by serially passaging tumors in nude mice in presence of gefitinib until resistance was acquired. EMP-1 was identified as a surface biomarker whose expression correlated with acquisition of gefitinib resistance. EMP-1 expression was further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations. This report suggests the role of the adhesion molecule, EMP-1, as a biomarker of gefitinib clinical resistance, and further suggests a probable cross-talk between this molecule and the EGFR signaling pathway.

Original languageEnglish (US)
Pages (from-to)11858-11863
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number33
DOIs
StatePublished - Aug 16 2005

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Keywords

  • EGF receptor
  • HER-kinase axis
  • Non-small cell lung cancer
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • General

Cite this

Jain, A., Tindell, C. A., Laux, I., Hunter, J. B., Curran, J., Galkin, A., Afar, D. E., Aronson, N., Shak, S., Natale, R. B., & Agus, D. B. (2005). Epithelial membrane protein-1 is a biomarker of gefitinib resistance. Proceedings of the National Academy of Sciences of the United States of America, 102(33), 11858-11863. https://doi.org/10.1073/pnas.0502113102