Home Blog of Signal Transduction Protein Tyrosine Kinase TAM receptors (Tyro-3,Axl,and Mertk) Axl Inhibitor R428 Induces Apoptosis of Cancer Cells by Blocking Lysosomal Acidification and Recycling Independent of Axl Inhibition

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Axl Inhibitor R428 Induces Apoptosis of Cancer Cells by Blocking Lysosomal Acidification and Recycling Independent of Axl Inhibition

R428 (BGB324) is an anti-cancer drug candidate under clinical investigation. It inhibits the receptor tyrosine kinase Axl and induces apoptosis of many types of cancer cells, but the relationship between the two has not been well established. We investigated the molecular mechanisms of the R428-induced apoptosis and found that R428 induced extensive cytoplasmic vacuolization and caspase activation, independent of its inhibitory effects on Axl. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophagosomes and lysosomes, and induced cell apoptosis. Inhibition of autophagy by autophagy inhibitors or autophagic gene-knockout alleviated the R428-induced vacuoles formation and cell apoptosis. Our study uncovered a novel function and mechanism of R428 in addition to its ability to inhibit Axl. These data will help to better direct the application of R428 as an anti-cancer reagent. It also adds new knowledge to understand the regulation of autophagy and apoptosis.

Related Products

Cat.No. Product Name Information
S2841 Bemcentinib (R428) Bemcentinib (R428, BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).

Related Targets

TAM receptors (Tyro-3,Axl,and Mertk)