Abstract 5660: Anti-proliferation effect of polo-like kinase-4 inhibitor in ovarian cancer via AKT/mTOR/p70S6K pathway

Abstract

Abstract Background: Chromosomal instability is a hallmark in epithelial ovarian cancer. Polo-like kinases (PLK) play a vital role in cell cycle regulation. In particular, PLK4 is crucial in centriole duplication. PLK4 overexpression causes defect in cytokinesis, which in turn leads to aneuploidy and mitosis catastrophe. Previous studies showed that PLK4 inhibitors are effective against cell growth in different cancers like breast cancer and lung cancer. We hypothesize that the AKT/mTOR and p70S6K pathway is involved in this mechanism. Methods: The importance of cell proliferation of PLK4 was assessed by its inhibition in ovarian cancer cell lines and patient-derived organoids by CFI-400945. RNA sequencing was performed. The effects of PLK4 inhibition on the AKT/mTOR and p70S6K pathway was demonstrated by qPCR and western blot. Correlation of the mRNA expression level with the IC50 of CFI-400945 in ovarian cancer cell lines. Results: PLK4 inhibition led to reduced cell proliferation in ovarian cancer cells based on XTT and colony formation assays. The anti-proliferative effect was further confirmed in 12 patient-derived organoids using ATP bioluminescent assay. RNA sequencing showed that PLK4 inhibition led to downregulation of the AKT/mTOR/p70S6K pathway. It was found that the most sensitive cell line had the highest mRNA expression of mTOR and p70S6K, while those less sensitive had lower mTOR and p70S6K mRNA expression. Treatment with CFI-400945 showed a reduction of total and phosphorylated forms of AKT, mTOR and p70S6K in a dose-dependent level. Combined treatment with metformin, a drug that had mTOR inhibition effect, showed a synergistic effect in one ovarian cancer cell line. Conclusion: PLK4 inhibition caused reduced cell proliferation in in vitro and ex vivo assays, and this was accompanied by a downregulation of the AKT/mTOR/p70S6K pathway. This suggested that this pathway might be one of the downstream effector pathways of PLK4. Citation Format: Ka Yu Tse, Wai Sun Chan, Moxil Xuetang Mo, Horace Hok Yeung Lee, Philip Pun Ching Ip, Tak Wah Mak. Anti-proliferation effect of polo-like kinase-4 inhibitor in ovarian cancer via AKT/mTOR/p70S6K pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5660.