Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

Abstract

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.

ADAM17 Inhibition Increases the Impact of Cisplatin Treatment in Ovarian Cancer Spheroids

“…Even though the blocking of ADAM17 and its multitude of substrates and downstream effectors might lead to broader effects, several studies revealed that the inhibition of single downstream pathways leads to the concomitant activation of compensator pathways of other RTKs and is not sufficient to reduce tumor growth [ 46 ]. Novel studies consider blocking several pathways, for example, the combination of the tyrosine kinase inhibitor sunitinib with phosphoinositide 3-kinase/protein kinase B/Akt/mechanistic Target of Rapamycin (PI3K/AKT/mTOR) inhibitor, everolimus, and proto-oncogene tyrosine-protein kinase SRC inhibitor, dasatinib, showed synergistic antitumor activity in an ovarian cancer model [ 67 ]. ADAM17 works upstream of all these pathways and thus might be a valuable alternative target to reduce tumor growth and overcome drug resistance.…”

Comprehensive analysis for the immune related biomarkers of platinum-based chemotherapy in ovarian cancer

“…Wang et al. found SRPK1 participated in cisplatin resistance associated with lncRNA UCA1 in human OC cells [53] . Another reported showed that the UCA 1 / miR-99b-3p / SRPK 1 axis may be a novel target for the treatment of ovarian cancer [54] .However, further functional analysis and the prognostic impact of related lncRNA on OC patients with platinum-based chemotherapy resistance need subsequent analysis, which can be supplemented as future research prospects.…”

Clinical analysis and literature review of a case of ovarian clear cell carcinoma with PIK3CA gene mutation: A case report

“…Some PI3K and mTOR inhibitors, such as everolimus, are in clinical trials. [ 45 , 46 ] Given the inherent complexity of this pathway, targeting just one component of the pathway at a time has proven futile thus far; as a result, combination treatment with chemotherapies and antiangiogenic drugs has been adopted, and the results show improved prognosis. [ 47 , 48 ] Despite its association with increased IL-6 secretion, which promotes OCCC development, PIK3CA mutation has, interestingly, been linked to good prognosis and improved overall survival in OCCC patients.…”