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.
Prachi Patidar, Kritika Jangir, Chainsee Saini et al.· Cell Communication and Signa...· 0 citations
While several G2/M oncogenes are known to promote tumor progression, their coordinated tumor-suppressive networks antagonizing this axis and their regulatory and immunological contexts remain poorly defined.
We performed a multi-layered integrative analysis combining correlation profiling (UALCAN and ENCORI), multi-endpoint survival analysis (KM Plotter: OS, FPS, PPS across pan-lung, LUAD, and smoker cohorts), and transcriptomic refinement using TNMplot. A miRNA–mRNA regulatory network was constructed via miRNet, refined using UALCAN expression filtering, KM survival, and CancerMIRNome ROC analysis, followed by ENCORI-based miRNA–gene correlation. Direct miRNA–mRNA and lncRNA–miRNA binding affinities were assessed using IntaRNA. lncRNAs associated with the key miRNA were identified via Enrichr, filtered by expression, correlation, and survival, and validated by binding and gene correlation analyses. Finally, immune cell correlations were evaluated using GSCA, and an integrated ROC model was generated in R.
We identified a high-confidence panel of six tumor suppressors (CBX7, CD81, CRY2, CYBRD1, NR3C2, REEP5) and six G2/M oncogenes (AURKA, AURKB, BUB1, FOXM1, MELK, TTK) based on correlation, survival, and TNMplot criteria. hsa-let-7b-5p emerged as a central regulatory miRNA (AUC = 0.89) positively correlated with tumor suppressors and predicted to bind all six oncogenes. TMPO-AS1 was identified as an oncogenic lncRNA antagonizing hsa-let-7b-5p via strong binding (–15.85 kcal/mol) and negative correlation with tumor suppressors. An integrated lncRNA-miRNA-mRNA ROC model achieved an AUC ≈ 0.97. Immune analysis revealed reciprocal patterns: tumor suppressors correlated with MAIT, NKT, and Tfh cells and inversely with exhausted cells and nTregs, whereas oncogenes showed the opposite trend with the same.
This study defines a robust G2/M -associated regulatory framework in LUAD, characterized by reciprocal dysregulation of oncogenes and tumor suppressors and associated with the predicted TMPO-AS1–hsa-let-7b-5p regulatory network, which is linked to a less immunosuppressive tumor microenvironment, offering potential prognostic and therapeutic implications in LUAD.
Prerna Vats, B. Baweja, Chainsee Saini et al.· BMC Pulmonary Medicine· 0 citations