The Receptor Tyrosine Kinase AXL in Cancer Progression

Abstract

The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy.

Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

“…[4][5][6][7][8] AXL has a single specific ligand, growth arrest-specific 6 (GAS6) protein, which has also been implicated in poor prognosis, metastasis, and drug resistance in several forms of cancer. 1,4 The expression of GAS6 is widespread in many tissues and cells, including immune cells, endothelial cells, vascular smooth muscle cells, bone marrow cells, adipocytes, platelets, and various cancer cells. 9 Signaling via the TAM kinase receptors activate different downstream signaling cascades and regulate diverse functions, including cell migration, adhesion, inflammation, cell growth, survival, and other cell type-specific functions.…”

“…AXL, a member of the TAM family of receptor tyrosine kinases, is highly expressed in primary tumors and metastases in comparison with normal tissues and plays a role in tumor proliferation and survival, metastasis, and drug resistance . AXL has a single specific ligand, growth arrest‐specific 6 (GAS6) protein, which has also been implicated in poor prognosis, metastasis, and drug resistance in several forms of cancer . The expression of GAS6 is widespread in many tissues and cells, including immune cells, endothelial cells, vascular smooth muscle cells, bone marrow cells, adipocytes, platelets, and various cancer cells .…”

AXL Controls Directed Migration of Mesenchymal Triple-Negative Breast Cancer Cells

“…AXL can be activated by its ligand, the growth arrest specific protein 6 (GAS6) [24,25] or through its interaction with other transmembrane receptors such as human epidermal growth factor receptor 1 (EGFR) in TNBC [26]. AXL activation leads to its autophosphorylation, switching on downstream signaling cascades such as PI3K/AKT, MAPK, JAK/STAT, SRC and RHO pathways [27,28]. The involvement of AXL in EMT has been largely documented [29][30][31][32][33], and it is likely through this property that AXL plays a role in migration, invasion, drug resistance and metastases [28,29,[34][35][36][37][38][39][40][41][42][43][44][45].…”

Aberrant claudin-6–adhesion signal promotes endometrial cancer progression via estrogen receptor α

“…To identify downstream molecules that expression is altered by the CLDN6 signaling, we next compared, using RNA sequencing, the transcriptome in Ishikawa: CLDN6 cells with that in Ishikawa cells ( Figure 7A ). Among the CLDN6-activated genes, the gene products associated with malignant phenotypes, including ADAMTS18 (a disintegrin and metalloproteinase with thrombospondin motifs; 24) and the transmembrane receptor-associated tyrosine kinase AXL (25), as well as the soluble factors CTGF (Connective tissue growth factor; 26), CXCL1 (C-X-C motif ligand 1; 27), FGFBP1 (Fibroblast growth factor binding protein 1; 28), NRG1 (Neuregulin 1; 29), NTN4 (Netrin 4; 30) and TGFB2 (Tumor growth factor beta 2; 31), were detected. We then by semi-quantitative RT-PCR clarified the expression of these eight genes in Ishikawa, Ishikawa: CLDN6 , Ishikawa: ESR1 −/− and Ishikawa: CLDN6:ESR1 −/− cells ( Figure 7B ).…”