Litt repetisjon:
Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer
Published: 15 September 2021
https://www.mdpi.com/1422-0067/22/18/9953 (DOI)
Receptor tyrosine kinases (RTKs) are cell surface receptors that mediate a number of physiological responses and homeostasis. However, gene amplification, overexpression, and activating mutations of RTKs are often associated with cancer development, pro- gression, and metastasis and have served as pharmacological targets in cancer treatment. Axl belongs to the TAM (Tyro3, Axl, MerTK) subfamily of the RTKs. Physiologically, the Gas6/Axl pathway plays an important role in platelet aggregation and vessel integrity. Axl knockout in germ cells does not result in embryonic lethality. The growth arrest specific 6 (Gas6) protein belongs to the vitamin K-dependent family of proteins and is a high affinity ligand for Axl. Overexpression and activation of Axl are widely observed in various cancer types and have been implicated in multiple steps of cancer pathogenesis. In addition, high Axl expression and activation are associated with poor prognosis, outcome, and resistance to therapy in cancer patients. As such, the Gas6/Axl pathway has gained attention as a promising therapeutic target for drug development in multiple tumor types.
Axl was first isolated from chronic myelogenous leukemia cells in 1988.
Briefly, Axl is overexpressed in many cancer types and is associated with therapeutic resistance, poor clinical prognosis, and worse outcome. Axl also mediates key components of the metastatic cascade, including, but not limited to, epithelial-to-mesenchymal transition, migration and invasion, proliferation, survival, stemness, angiogenesis, and immunesion.
Bemcentinib (BGB324, R428)
Bemcentinib is a highly specific and selective Axl inhibitor with an IC50 of 14 nM in cellular assays. This agent has been widely studied in the laboratory in a variety of cancer models, including breast, prostate, lung, pancreatic, and ovarian cancer, and has been shown to decrease tumor cell migration, invasion, and colony forma- tion in vitro and impair primary tumor growth, immune cell infiltration, and metastasis in vivo. Axl inhibition alters the expression patterns of EMT markers, upregulating epithelial markers, such as E-cadherin, and downregulating mesenchymal markers, such as N-cadherin, ZEB1, Snail, Slug, Twist, and MMP9. Furthermore, several studies have demonstrated that Axl inhibition reverses the therapeutic resistance of certain chemothera- pies. Axl has also been associated with immune evasion, and the systematic treatment of tumor-bearing mice with bemcentinib has led to a reduction in tumor-infiltrating host cells, most notably cells of the myeloid lineage
Bemcentinib entered clinical trials as the first Axl-specific inhibitor and is undergoing Phase I/II clinical trials for melanoma, non-small-cell lung cancer (NSCLC), mesothe- lioma, acute myeloid leukemia, glioblastoma, and pancreatic adenocarcinoma (Clinical Trial Identification Numbers: NCT02872259; NCT02922777; NCT03184571; NCT03654833; NCT03824080; NCT03965494; NCT03649321). A Phase II clinical trial of bemcentinib in combination with pembrolizumab for patients with triple-negative breast cancer has been completed, but the results are not yet available (Clinical Trial Identification #: NCT03184558).
