KIF18A (Kinesin Family Member 18A)

Mechanistically, ATX020 blocks KIF18A's plus-end movement on spindle fibers, increasing spindle length, resulting in chromosomal mis-segregation, aneuploidy, and DNA damage. Our findings suggest that ATX020 inhibits CIN+ HGSOC cells mainly by inducing mitotic arrest and DNA damage, disrupting KIF18A's function crucial for mitosis.

ATX020 is a potent KIF18A inhibitor with a high degree of kinesin selectivity, favorable in vitro and in vivo ADME properties, and robust efficacy in the OVCAR-3 cell-derived xenograft (CDX) model. A high-resolution crystal structure of the KIF18A-tubulin complex and an experimentally guided model of ATX020 bound to the complex are provided, supporting future structure-based drug design of KIF18A inhibitors.

This study reveals that KIF18A is upregulated in OS, particularly in metastatic cases, and is linked to poor clinical outcomes. Functional experiments confirm that KIF18A promotes proliferation, migration, and invasion of OS cells while suppressing apoptosis. In vivo experiments reveal that KIF18A knockdown strongly inhibits tumor growth. KIF18A expression correlates with dysregulation of key oncogenic pathways, an immunosuppressive microenvironment, and potential immunotherapy resistance. These results highlight KIF18A's role as a pivotal oncogene in OS progression and suggest its promise as both a prognostic biomarker and a therapeutic target.

Taken together, our findings suggest that KIF18A plays crucial roles in promoting the progression and survival of gemcitabine-resistant CCA cells, partly by modulating PI3K/Akt/mTOR and NF-κB pathways. Therefore, despite its lack of prognostic utility, KIF18A represents a promising therapeutic target for improving treatment outcomes in CCA patients, especially those who do not respond to gemcitabine treatment.

Therefore, KIF18A may promote the proliferation, invasion, and EMT of liver cancer cells by activating the 5-LOX-dependent arachidonic acid pathway. This study provides a new strategy for the prognostic assessment and targeted therapy of HCC and reveals the important role of KIF18A in the development of liver cancer.

In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5). These findings suggest that differential expression and activity of Anapc5 and Anapc7 may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies.

Our findings suggest that the MEX3 family is associated with the prognosis of hepatocellular carcinoma patients and contributes to disease progression by modulating the cell cycle and protein post-transcriptional modifications. Furthermore, this family is related to the tumor microenvironment, particularly in hypoxia and immune responses, which holds significant value for predicting liver cancer outcomes.

[This retracts the article DOI: 10.1155/2019/6383685.].

RT-qPCR confirmed significant upregulation of MCM10, KIF18A, CDC45, and PLK4 in HCC tissues (p< 0.05). This study successfully identified eight prognostic genes (MCM10, CEP55, KIF18A, ORC6, KIF23, CDC45, CDT1, and PLK4), which provided new directions for exploring the potential pathogenesis and clinical treatment research of HCC.

This multi-omics study provides insights into the asthma-lung cancer link and presents a promising prognostic model for lung cancer based on asthma-related genes. The model's association with immune features suggests its potential utility in immunotherapy patient selection.

Finally, targeting KIF18A enhanced PD-1 blockade efficiency in CIN+ colorectal tumors through T cells. Our data elucidated a novel role of KIF18A in antitumor immunity of CIN+ colorectal cancer.

Knockout of JAK1 in HNSCC increases cell survival by enhancing the DNA damage-induced G2 arrest, and both knockout and JAK1 inhibition with abrocitinib prevent subsequent formation of radiation-induced micronuclei...Given this insight, we evaluated Kif18a inhibition as an approach to exacerbate mitotic stress and enhance the efficacy of radiation. These studies establish Kif18a inhibition as a novel strategy to counteract therapeutic resistance to DNA damage mediated by G2 cell cycle arrest.