Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15.

Purpose: Focal adhesion kinase is an important survival signal in cancer. Recently, we demonstrated that the autophosphorylation inhibitor of FAK, Y15, effectively inhibited cancer cell growth. We detected many cancer cell lines sensitive to Y15 and also detected several cell lines such as colon cancer Lovo-1 and thyroid K1 more resistant to Y15.

Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy.

Focal adhesion kinase (FAK) increasingly has been implicated in cancer growth and progression. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that blocks the Y397 autophosphorylation site. FAK inhibitor, Y15 decreased Y397 FAK in different colon cancer cells lines in a dose-dependent manner.

FAK and HAS inhibition synergistically decrease colon cancer cell viability and affect expression of critical genes.

Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation.

Inhibition of hyaluronan synthase-3 decreases subcutaneous colon cancer growth by increasing apoptosis.

Hyaluronan (HA) and hyaluronan synthases (HAS) have been implicated in cancer growth and progression. We previously have shown that HAS3 and HA mediate tumor growth in SW620 colon cancer cells, but the mechanism remains poorly understood. In addition, the effect of HAS3 inhibition on tumor growth with other cells lines has not been explored.

Evolving therapies and FAK inhibitors for the treatment of cancer.

Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting.