Defactinib is a selective, and orally active focal adhesion kinase (FAK) inhibitor [1].

FAK is a nonreceptor tyrosine kinase involved in many oncogenic pathways. Increased expression of FAK has been observed in a number of tumor types, including breast, colon, and ovarian cancers. It has been reported that FAK inhibition can sensitize cancer cells to chemotherapy [1].

In Taxane-sensitive (HeyA8) and Taxane-resistant (HeyA8-MDR) cell lines, Defactinib at 0 ~ 10 μM significantly inhibited pFAK (Tyr397) expression in a dose-dependent manner. In addition, simultaneous exposure to doses of Paclitaxel and Defactinib at ratios of 1:1000 for HeyA8 and 1:10 for HeyA8-MDR showed a synergistic inhibitory effect on cell growth [1].

In mice bearing HeyA8 tumors, there was a 97.9% reduction in tumor weight by the combination therapy (Defactinib: 25 mg/kg orally twice daily, Paclitaxel: 2.5 mg/kg intraperitoneally weekly), compared with an 87.4% reduction in tumor weight by Paclitaxel monotherapy. In the SKOV3ip1 model, a 92.7% tumor weight reduction was observed in the combination group (Defactinib: 25 mg/kg orally twice daily, Paclitaxel: 2 mg/kg intraperitoneally weekly) [1].

Reference:

[1]. Kang Y, Hu W, Ivan C, et al. Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. Journal of the National Cancer Institute, 2013, 105(19): 1485-1495.