Increasing Antitumor Activity of JAK Inhibitor by Simultaneous Blocking Multiple Survival Signaling Pathways in Human Ovarian Cancer

Abstract

Many signaling pathways, including the JAK/STAT3 pathway, are aberrantly activated and associated with ovarian cancer growth and progression. However, inhibition of STAT3 pathway alone was not sufficient to effectively block human ovarian cancer cell survival in vitro, which could be due to the activation and compensation of multiple survival pathways. In this study, we investigated a strategy that can enhance antitumor activity of JAK/STAT3 inhibitor by combining with inhibitors targeting other growth and survival pathways. We found that the in vitro activity of JAKi was remarkably increased when additional survival pathway was blocked. Blocking SRC pathway with SRC inhibitor (SRCi) increased the efficacy of JAKi more effectively than blocking AKT or MAPK pathway. The increased activity of JAKi in combination with SRCi is synergistic and associated with attenuation of p-STAT3, p-SRC, p-AKT and p-MAPK and increased inhibition of p-AKT. Simultaneous blockade of multiple survival pathways by combining JAKi with both AKT inhibitor (AKTi) and MEK inhibitor (MEKi) also resulted in a synergistic inhibition of cell survival. Furthermore, the combined treatment of JAKi and SRCi led to an increased apoptosis and greater inhibition of tumor growth and ascites formation. Taken together, our results demonstrate that the antitumor efficacy of JAKi is improved most effectively when combined with SRCi, providing a potential combination strategy for the treatment of advanced ovarian cancer.