Abstract SY22-01: A strategy to intervene mitotic kinases to induce mitotic catastrophe in cancer cells

Abstract

Abstract Chromosomal instability (CIN) is an outstanding feature of cancer, which relates to intratumor heterogeneity, therapeutic resistance, and poor prognosis. While cancer cells can proliferate with CIN, experimentally induced aneuploidy is known to suppress cell growth, leading to the idea that extreme ploidy changes are detrimental to cancer cells. One of the major etiologies of CIN is abnormal kinetochore microtubule attachments, followed by chromosome missegregation. To avoid this, cells have evolved a robust system including two molecular networks for stabilizing and destabilizing microtubule attachments. Two mitotic kinases are involved in this system which have opposite but balanced mode of actions. We previously found that a wide range of cancer cells are defective for destabilization and results in an elevated rate of missegregation. In this study, we aimed to manipulate this kinase balance and found that weighing the balance to stabilizers can cause catastrophic chromosome segregation in mitosis, and such effect could be induced predominantly in cancer cells. These findings prompted us to undertake a screen for small molecules targeting the balanced activity of mitotic kinases. Citation Format: Motoko Takahashi, Minji Jo, Nana Kamakura, Chang Liu, Utako Kato, Toru Hirota. A strategy to intervene mitotic kinases to induce mitotic catastrophe in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY22-01.