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Review
. 2014 Oct 30;5(20):9546-63.
doi: 10.18632/oncotarget.2542.

AXL kinase as a novel target for cancer therapy

Xiaoliang Wu  1 , Xuewen Liu  2 , Sanjay Koul  3 , Chang Youl Lee  4 , Zhenfeng Zhang  1 , Balazs Halmos  3
Affiliations
Review

AXL kinase as a novel target for cancer therapy

Xiaoliang Wu et al. Oncotarget. .

Abstract

The AXL receptor tyrosine kinase and its major ligand, GAS6 have been demonstrated to be overexpressed and activated in many human cancers (such as lung, breast, and pancreatic cancer) and have been correlated with poor prognosis, promotion of increased invasiveness/metastasis, the EMT phenotype and drug resistance. Targeting AXL in different model systems with specific small molecule kinase inhibitors or antibodies alone or in combination with other drugs can lead to inactivation of AXL-mediated signaling pathways and can lead to regained drug sensitivity and improved therapeutic efficacy, defining AXL as a promising novel target for cancer therapeutics. This review highlights the data supporting AXL as a novel treatment candidate in a variety of cancers as well as the current status of drug development targeting the AXL/GAS6 axis and future perspectives in this emerging field.

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Figures

Figure 1
Figure 1. Structure, activation and signaling pathways of AXL
(A) AXL consists of two immunoglobulin-like (Ig) domains and dual fibronectin type III (FNIII) repeat domains and a kinase domain. Gas6 contains a γ-carboxyglutamic acid (Gla) domain, a loop region, four EGF-like repeats and two C-terminal globular laminin G-like (LG) domains. (B) AXL can be activated by ligand-dependent dimerization, ligand-independent dimerization, and interaction between two monomers on neighboring cells and heteromeric dimerization with a non-TAM receptor. (C) AXL plays important roles in cell proliferation, survival, migration, and the inflammatory process via different signaling pathways.
Figure 2
Figure 2. EGFR and AXL/MET switch plays critical roles in acquired EGFR TKI resistance and correlated epithelial-mesenchymal transition (EMT)
(A) EGFR TKI sensitive cells are EGFR signal dependent in survival and proliferation. (B) EGFR and AXL collectively regulate survival and proliferation in acquired EGFR TKI resistant cells. (C) A switch from an EGFR pathway dependent signal transduction pattern to an AXL/MET complex dependent pattern plays critical roles in acquired EGFR TKI resistance correlated EMT. AXL/MET over-expression, GAS6/HGF up-regulation, MET amplification, and AXL/MET might mediate uncoupling of EGFR activity from its kinase function and are reported causes of this switch to EGFR signaling independence.
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