Abstract
Many signaling pathways are dysregulated in cancer cells and the host tumor microenvironment. Aberrant receptor tyrosine kinase (RTK) pathways promote cancer development, progression, and metastasis. Hence, numerous therapeutic interventions targeting RTKs have been actively pursued. Axl is an RTK that belongs to the Tyro3, Axl, MerTK (TAM) subfamily. Axl binds to a high affinity ligand growth arrest specific 6 (Gas6) that belongs to the vitamin K-dependent family of proteins. The Gas6/Axl signaling pathway has been implicated to promote progression, metastasis, immune evasion, and therapeutic resistance in many cancer types. Therapeutic agents targeting Gas6 and Axl have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination therapy. This review examines the current state of therapeutics targeting the Gas6/Axl pathway in cancer and discusses Gas6- and Axl-targeting agents that have been evaluated preclinically and clinically.
Highlights
growth arrest specific 6 (Gas6)/Axl Signaling Pathway in Receptor tyrosine kinases (RTKs) are cell surface receptors that mediate a number of physiological responses and homeostasis
The results showed that treatment with AVB-500 decreases Gas6-induced Axl and Src phosphorylation, tumor vessel density, tumor growth, and metastatic burden [49,50,51]
Receptor tyrosine kinases have served as pharmacological targets in cancer treatment due to their frequent dysregulations, including gene amplifications, overexpression, and activating mutations, which promote tumor development, progression, and metastasis
Summary
Gas6/Axl Signaling Pathway in Receptor tyrosine kinases (RTKs) are cell surface receptors that mediate a number of physiological responses and homeostasis. The N-terminus Gla domain mediates binding to phosphatidylserine expressed on cell. Another study strated that Axl mediates cell invasion through the regulation of lysosome peripheral disdemonstrated that. The Gas6/Axl pathway upregulates pro-tumorigenic functions, such as immune evasion, survival, liferation, drug resistance, angiogenesis, epithelial-to-mesenchymal transition (EMT), migration, and invasion. In FAK-depleted pericytes, activated Pyk increases Gas transcript levels and signals via the Gas6/Axl/Akt/Cyr pathway to promote tumor cell proliferation and angiogenesis [34,35]. Axl-expressing leukemia-associated macrophages contribute to immune suppression and impair the functions of NK- and T-cell-mediated tumor cell killing [43]
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