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Review
. 2017 Mar;19(3):19.
doi: 10.1007/s11912-017-0579-4.

Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies

Marie Schoumacher  1 , Mike Burbridge  2
Affiliations
Review

Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies

Marie Schoumacher et al. Curr Oncol Rep. 2017 Mar.

Abstract

A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.

Keywords: AXL; Cancer; Drug resistance; Epithelial-to-mesenchymal transition; Immunomodulation; MER.

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Conflict of interest statement

Conflict of Interest

Marie Schoumacher is an employee of Servier Laboratories. Mike Burbridge is an employee of Servier Laboratories.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Figures

Fig. 1
Fig. 1
AXL and MER signaling networks in tumor cells. Schematic representing the major signaling networks activated upon binding of GAS6 with its TAM receptor in tumor cells. Affinity of GAS6 for AXL is higher than that for MER. Tyrosine docking sites in AXL are represented. Diverse adaptor proteins mediate activation of specific signaling pathways, involved in proliferation, migration, and survival. Potential direct and indirect phosphorylation biomarkers of AXL activity (pharmacodynamic markers) are indicated by yellow stars. Crosstalk between AXL and other RTKs is exemplified by the dimerization with EGFR and MET. Signaling implicated in the regulation of the immune response is depicted by blue arrows
See this image and copyright information in PMC

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