Investigator
The University Of Osaka
PI3K/mTOR Dual Inhibitor GSK458 and Arsenic Trioxide Exert Synergistic Antitumor Effects against Ovarian Clear-Cell Carcinoma
Abstract Ovarian clear-cell carcinoma (OCCC), particularly advanced or recurrent settings, is generally resistant to platinum-based chemotherapy, warranting novel therapeutic strategies. Mutations in the PI3K/AKT/mTOR pathway are frequently reported in OCCC. Therefore, we hypothesized that the PI3K/mTOR dual inhibitor, GSK458, and arsenic trioxide (As2O3) may exert synergistic antitumor effects on OCCC. We investigated the effects of GSK458, As2O3, and the combination of GSK458 and As2O3 on cell viability, colony formation, and apoptosis in seven OCCC cells. Mechanistically, transcriptomic differences were assessed among the groups. Additionally, their antitumor effects were evaluated on the three-dimensional cultures of OCCC patient-derived xenografts as well as in vivo. Low-dose combination of GSK458 and As2O3 exerted synergistic antitumor effects in vitro. Viability of the three-dimensional OCCC patient-derived xenograft cultures treated with the combination of GSK458 and As2O3 decreased to 23.8% of that of the control. RNA sequencing revealed that the mechanism was associated with cell cycle and DNA damage repair. The combination of GSK458 and As2O3 synergistically inhibited the PI3K/AKT/mTOR pathway and angiogenesis and increased apoptosis. Compared with any monotherapy, the combination treatment significantly suppressed tumor growth in vivo, thereby enhancing survival. Overall, our findings highlight the potential of the novel combination of GSK458 and As2O3 for OCCC treatment.
