Giving AXL the axe: targeting AXL in human malignancy

Abstract

The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation.

Figure 1

Spectrum of cellular processes regulated by AXL activity. AXL, following activation by its ligand GAS6 along with an interaction between GAS6 and phosphatidylserine (PtdSer), dimerises and cross-phosphorylates (yellow circle) its partner receptor. This activation regulates an array of cellular pathways as illustrated at the bottom of the figure. Inset: AXL activity plays a complex role in immune regulation that includes the inhibition of cytokine release, TLR signalling, and T-cell activation by antigen-presenting cells such as dendritic cells (above), as well as specific antitumor killing by natural killer cells (below).

Figure 2

Transcriptional and post-transcriptional regulation of AXL/AXL. (A) The promoter region upstream of the AXL transcriptional start site (TSS) highlights binding sites for transcription factors, including hypoxia responsive element (HRE) for HIF1α, MZF1, and AP1. The promoter region also contains numerous Sp1 binding sites, which are sites of potential repressive methylation events (red). (B) AXL is a target for Cbl-B-dependent ubiquitination (Ub) resulting in proteasomal degradation. (C) AXL 3' untranslated region (UTR) contains target sequences for miRs, including miR-34 (pictured) and miR-199a/b, resulting in reduced translation via ribosomal blockade and increased RNA degradation. (D) Data adapted from cBioPortal show the infrequency of AXL genetic alterations in selected tumour types. Frequencies are as follows: breast cancer, 2.2% (18/816); head and neck squamous cell carcinoma, 1.4% (4/279); lung adenocarcinoma, 3% (7/230); lung squamous cell carcinoma, 2.8% (5/178); and acute myeloid leukaemia, 0% (0/191).