Defactinib (VS-6063) at doses of 25 mg/kg twice daily significantly reduces pFAK (Tyr397) expression at 3 hours, with expression levels rebounding by 24 hours. This dosage regimen of 25 mg/kg twice daily is therefore chosen for future therapy studies. In these studies, female nude mice with HeyA8 tumors in the peritoneal cavity are allocated into four groups (n=10 per group): 1) control group receiving oral vehicle twice daily and weekly intraperitoneal phosphate-buffered saline; 2) Defactinib at 25 mg/kg orally twice daily; 3) PTX administered intraperitoneally weekly; 4) a combination of Defactinib at 25 mg/kg orally twice daily and weekly PTX intraperitoneally. PTX alone achieves an 87.4% reduction in tumor weight in the HeyA8 model, while the combination therapy shows the most significant decrease, with a 97.9% reduction in tumor weight (P=0.05 versus PTX alone). In the SKOV3ip1 model, the combination therapy leads to a 92.7% reduction in tumor weight compared to PTX alone (P<0.001)^[1].

Defactinib (VS-6063) suppresses FAK phosphorylation at the Tyr397 site in both time- and dose-responsive ways. RPPA analysis reveals that Defactinib decreases AKT and YB-1 levels in taxane-resistant cell lines. Defactinib's inhibition of pFAK (Tyr397) expression across all cell lines is statistically significant and dose-dependent. Within 3 hours, Defactinib reduces pFAK (Tyr397) expression, which starts to reappear by 48 hours^[1].