The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma

Hector Alvarez, Elizabeth A. Montgomery, Collins Karikari, Marcia Canto, Kerry B. Dunbar, Jean S. Wang, Georg Feldmann, Seung Mo Hong, Michael C. Haffner, Alan K. Meeker, Sacha J. Holland, Jiaxin Yu, Thilo J. Heckrodt, Jing Zhang, Pingyu Ding, Dane Goff, Rajinder Singh, Juan Carlos Roa, Arivusudar Marimuthu, Gregory J. RigginsJames R. Eshleman, Barry D. Nelkin, Akhilesh Pandey, Anirban Maitra

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Esophageal adenocarcinoma (EAC) arises in the backdrop of reflux-induced metaplastic phenomenon known as Barrett esophagus. The prognosis of advanced EAC is dismal, and there is an urgent need for identifying molecular targets for therapy. Serial Analysis of Gene Expression (SAGE) was performed on metachronous mucosal biopsies from a patient who underwent progression to EAC during endoscopic surveillance. SAGE confirmed significant upregulation of Axl "tags" during the multistep progression of Barrett esophagus to EAC. In a cohort of 92 surgically resected EACs, Axl overexpression was associated with shortened median survival on both univariate (p < 0.004) and multivariate (p < 0.036) analysis. Genetic knockdown of Axl receptor tyrosine kinase (RTK) function was enabled in two EAC lines (OE33 and JHEsoAd1) using lentiviral short hairpin RNA (shRNA). Genetic knockdown of Axl in EAC cell lines inhibited invasion, migration and in vivo engraftment, which was accompanied by downregulation in the activity of the Ral GTPase proteins (RalA and RalB). Restoration of Ral activation rescued the transformed phenotype of EAC cell lines, suggesting a novel effector mechanism for Axl in cancer cells. Pharmacological inhibition of Axl was enabled using a small molecule antagonist, R428 (Rigel Pharmaceuticals). Pharmacological inhibition of Axl with R428 in EAC cell lines significantly reduced anchorage-independent growth, invasion and migration. Blockade of Axl function abrogated phosphorylation of ERBB2 (Her-2/neu) at the Tyr877 residue, indicative of receptor crosstalk. Axl RTK is an adverse prognostic factor in EAC. The availability of small molecule inhibitors of Axl function provides a tractable strategy for molecular therapy of established EAC.

Original languageEnglish (US)
Pages (from-to)1009-1018
Number of pages10
JournalCancer Biology and Therapy
Volume10
Issue number10
DOIs
StatePublished - Nov 15 2010

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Keywords

  • Axl
  • Barrett esophagus
  • Ral GTP
  • SAGE

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Alvarez, H., Montgomery, E. A., Karikari, C., Canto, M., Dunbar, K. B., Wang, J. S., Feldmann, G., Hong, S. M., Haffner, M. C., Meeker, A. K., Holland, S. J., Yu, J., Heckrodt, T. J., Zhang, J., Ding, P., Goff, D., Singh, R., Roa, J. C., Marimuthu, A., ... Maitra, A. (2010). The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biology and Therapy, 10(10), 1009-1018. https://doi.org/10.4161/cbt.10.10.13248