TTK: A Promising Target in Malignant Tumors

Abstract

TTK is a dual-specific protein kinase that phosphorylates serine and threonine. The spindle assembly checkpoint (SAC) acts as a molecular monitoring mechanism that regulates mitosis and ensures accurate separation of chromosomes. TTK is a key regulator of the SAC. Activated TTK localizes to kinetochores and activates SAC function. Simultaneously, TTK promotes error correction by phosphorylating several substrates. When all chromosomes are correctly aligned, TTK is separated from kinetochores, and SAC function is turned off, thus initiating the anaphase of mitosis. TTK is highly expressed in various malignant tumors and is negatively associated with survival. TTK inhibition inhibits malignant tumor cells growth, and the combination of TTK inhibition and chemotherapy enhances anti-tumor effects in vitro. The combination of TTK inhibitors and chemotherapy increased efficacy without increasing adverse reactions. The addition of TTK inhibition also enhanced the effect of radiotherapy both in vitro and in vivo. The combination of TTK inhibition and radiotherapy results in more DNA double-strand damage and mitotic catastrophe, with the involved mechanisms including homologous recombination pathways and non-homologous end-joining pathways. The mechanism of combination therapy is complex and requires further study. Five small-molecule TTK inhibitors have been tested in clinical trials and were used in combination with paclitaxel because the combination could enhance the killing of cancer cells and alleviate side effects by reducing the drug dosage. Because of its high expression in malignant tumors, TTK is expected to be developed as an effective anti-tumor vaccine. TTK is a promising treatment target and further investigation is warranted.

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors

“…Targeting CDK4/6 with palbociclib could improve the sensitivity of TNBC cells to paclitaxel [10]. A TTK inhibitor in combination with paclitaxel prevents TNBC proliferation and growth [11]. Many therapeutic agents and monoclonal antibodies produced poor therapeutic outcomes or are currently under investigation [2,3,12], which makes it relevant to continue the search for novel, predictive, and prognostic biomarkers for TNBC in order to improve individualized therapy for this type of cancer.…”

“…Red, yellow, and green colors stand for high, moderate, and low methylation levels, respectively. The moderately methylated supercluster breaks up into several smaller clusters that incorporate moderate luminal B (modLumB), moderate TNBC (modTNBC), moderate HER2-enriched (modHER), and normal tissue (NORM) samples (MTypeHE annotation bar, as assigned previously[11]). EType annotation bar provides information about immunohistochemical BC molecular subtypes.…”