PI3K/mTOR dual inhibitor GSK458 and arsenic trioxide exert synergistic anti-tumor 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 phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin kinase (PI3K/AKT/mTOR) pathway are frequently reported in OCCC. Therefore, we hypothesized that the PI3K/mTOR dual inhibitor, GSK458, and arsenic trioxide may exert synergistic anti-tumor effects on OCCC. We investigated the effects of GSK458, arsenic trioxide, and the combination of GSK458 and arsenic trioxide on cell viability, colony formation, and apoptosis in seven OCCC cells. Mechanistically, transcriptomic differences were assessed among the groups. Additionally, their anti-tumor effects were evaluated on the three-dimensional cultures of OCCC patient-derived xenografts as well as in vivo. Low-dose combination of GSK458 and arsenic trioxide exerted synergistic anti-tumor effects in vitro. Viability of the three-dimensional OCCC patient-derived xenograft cultures treated with the combination of GSK458 and arsenic trioxide 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 arsenic trioxide synergistically inhibited the PI3K/AKT/mTOR pathway and angiogenesis and increased apoptosis. Compared to 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 arsenic trioxide combination for OCCC treatment.