The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma.
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 JH-EsoAd1) 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.
Hector
Alvarez
A
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Montgomery
Elizabeth A
EA
Karikari
Collins
C
Canto
Marcia
M
Dunbar
Kerry B
KB
Wang
Jean S
JS
Feldmann
Georg
G
Hong
Seung-Mo
SM
Haffner
Michael C
MC
Meeker
Alan K
AK
Holland
Sacha J
SJ
Yu
Jiaxin
J
Heckrodt
Thilo J
TJ
Zhang
Jing
J
Ding
Pingyu
P
Goff
Dane
D
Singh
Rajinder
R
Roa
Juan Carlos
JC
Marimuthu
Arivusudar
A
Riggins
Gregory J
GJ
Eshleman
James R
JR
Nelkin
Barry D
BD
Pandey
Akhilesh
A
Maitra
Anirban
A
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D000368:Aged; D000818:Animals; D001471:Barrett Esophagus / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D001567:Benzocycloheptenes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000077341:Lapatinib; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015996:Survival Rate; D014230:Triazoles / Q000494:pharmacology; D020725:ral GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D001567:Benzocycloheptenes; D036341:Intercellular Signaling Peptides and Proteins; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D014230:Triazoles; D020725:ral GTP-Binding Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C548378:bemcentinib
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