FAK (Focal adhesion kinase), a non-receptor tyrosine kinase, can regulate the cytoskeleton and is reported to have increased expression in a number of tumor types, including breast, colon and ovarian cancers. Defactinib is a selective FAK inhibitor which dose-dependently down-regulated pFAK (Tyr397) at concentration ranging in 10nM-10μM in taxane-sensitive HeyA8 cells and 0.1-10μM in taxane-resistant HeyA8-MDR cells. Co-incubation of 1μM Defactinib and paclitaxel could decrease the paclitaxel-induced expression of YB-1 and its phosphorylation at Ser102 site, which has a potential role in oncogenic and drug-resistance pathways, as well as restored the location of YB-1 to cytoplasm, in HeyA8-MDR cells. For AKT is required to phosphorylation and translocation of YB-1, the signaling of AKT pathway was also examined. The resulted show that Defactinib could downregulate p-YB-1 and its nuclear translocation in an AKT-dependent manner, as well as inhibit p-FAK-Y397 and p-AKT-S473 in taxane-resistant SKOV3 cells. This inhibition of YB-1 by Defactinib through FAK may downregulate the expression of CD44, a downstream target of YB-1 and a partial contributor to the PTX-resistant phenotype, in HeyA8-MDR cells. Combined therapy of paclitaxel with Defactinib >25 mg/kg orally twice a day resulted in greater reduction in tumor growth of PTX-resistant models, including HeyA8-MDR and SKOV3-TR xenografts[1].
作用机制
Defactinib is an ATP-competitive, reversible inhibitor of FAK.[2]
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