Targeting TTK signaling axis: chromosomal instability to tumor fitness

Abstract Threonine tyrosine kinase (TTK) also known as MonoPolar Spindle 1 (Mps1) is a core regulator of the spindle assembly checkpoint (SAC) that ensures accurate chromosome segregation during mitosis. While its canonical role in safeguarding genomic stability is well established, emerging evidence indicates that TTK is frequently overexpressed across a wide range of cancers, where it supports tumor cell survival under conditions of elevated chromosomal instability (CIN). This paradox highlights TTK's dual role as both a guardian of mitotic fidelity and a facilitator of tumor adaptability. Recent studies have demonstrated that pharmacological inhibition of TTK induces mitotic catastrophe by exacerbating chromosome mis-segregation, thereby selectively targeting cancer cells. Several small-molecule TTK inhibitors have entered clinical evaluation, particularly in combination with chemotherapeutic agents and radiotherapy. However, therapeutic responses remain heterogeneous, and the mechanistic basis of tumor-specific reliance on TTK across different cancer contexts remains poorly understood. This review consolidates current knowledge of TTK function beyond its canonical SAC activity, emphasizing its emerging roles in DNA damage response, epithelial-mesenchymal transition, and oncogenic signaling pathways. In addition, the review highlights critical unresolved questions, including the distinction between kinetochore and non-kinetochore functions, and the quantitative thresholds of TTK activity required for checkpoint maintenance. Finally, current advances in TTK-targeted drug development, challenges related to therapeutic selectivity and resistance, along with rational combination therapies and biomarker-guided therapeutic strategies have been summarized. Addressing these challenges will be critical for translating TTK biology into effective therapeutic interventions and for harnessing its potential in precision oncology.