Journal
CANCER BIOLOGY & THERAPY
Volume 10, Issue 10, Pages 1009-1018Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cbt.10.10.13248
Keywords
barrett esophagus; Axl; Ral GTP; SAGE
Categories
Funding
- NCI NIH HHS [R01 CA113669-06, R01 CA130938, R01CA134767, P01 CA134292-01A1, P50 CA062924, R01CA113669, R01 CA113669, R01 CA113669-07, R01 CA134767, P01 CA134292-02, P01 CA134292-03, R01CA130938, P01 CA134292, P50CA062924] Funding Source: Medline
- NIDDK NIH HHS [K23 DK068149, K23DK068149] Funding Source: Medline
- NINDS NIH HHS [R01NS052507, R01 NS052507] Funding Source: Medline
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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.
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