defactinib and Ovarian-Neoplasms

Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure-activity relationship (SAR) exploration identified 36 as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signaling in vitro. Treatment with 36 not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover, 36 inhibited tumor growth and metastasis, and no obvious adverse effects were observed during the in vivo study. These results revealed the potential of FAK inhibitor 36 for treatment of ovarian cancer.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; Focal Adhesion Kinase 1; Humans; Indans; Mice; Mice, Inbred BALB C; Mice, Nude; Microsomes, Liver; Molecular Structure; Neoplasms, Experimental; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Structure-Activity Relationship; Tumor Cells, Cultured

We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood.. We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test.. We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (χ²) = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006).. We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1-mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Focal Adhesion Kinase 1; Humans; Mice; Mice, Nude; Odds Ratio; Organic Chemicals; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrazines; Sulfonamides; Xenograft Model Antitumor Assays; Y-Box-Binding Protein 1

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Drug Resistance, Neoplasm; Female; Focal Adhesion Kinase 1; Humans; Organic Chemicals; Ovarian Neoplasms; Paclitaxel; Pyrazines; Sulfonamides; Y-Box-Binding Protein 1