Abstract
Simple SummaryOvarian cancer remains the most lethal gynecological cancer in women. There is a critical need to develop novel strategies that can be used to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single-targeted agents have shown limited antitumor activity in ovarian cancer. In this study, we found that combined treatment of several FDA-approved targeted drugs—sunitinib, dasatinib, and everolimus—results in simultaneous inhibition of multiple signaling pathways and a better anti-tumor activity than any single treatment. This combination also significantly improves efficacy of paclitaxel in human ovarian cancer. This study may provide a potential combination therapy for the treatment of advanced ovarian cancer.More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.
Highlights
Ovarian cancer remains the most lethal gynecological cancer in women
We investigated a novel strategy involving combination of several Food and Drug Administration (FDA)-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers
We found that any increased theor anti-tumor activity of paclitaxel, withdasatinib, the SDE combination increasing the efficacy of treatment synergistically increased the anti-tumor activity of paclitaxel, with the combination paclitaxel more effectively than any single or dual combination
Summary
Ovarian cancer remains the most lethal gynecological cancer in women. It is typically diagnosed at an advanced stage when the cancer has already spread into the peritoneal cavity [1,2,3].Cancers 2020, 12, 2586; doi:10.3390/cancers12092586 www.mdpi.com/journal/cancersThe current first-line treatment for ovarian cancer is cytoreductive surgery followed by taxane-platinum chemotherapy [3,4,5,6]. Ovarian cancer remains the most lethal gynecological cancer in women. It is typically diagnosed at an advanced stage when the cancer has already spread into the peritoneal cavity [1,2,3]. The current first-line treatment for ovarian cancer is cytoreductive surgery followed by taxane-platinum chemotherapy [3,4,5,6]. Maximum cytoreductive surgery is associated with the longest patient survival, especially when combined with intraperitoneal chemotherapy [7]. The initial response rate to standard therapy is greater than 70%, the majority of patients will eventually relapse and require further treatment [5]. Clinical studies of several chemotherapy agents, either alone or in combination, have demonstrated moderate response in patients with advanced and recurrent ovarian cancer
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