Advancing Cancer Therapy: The Role of KIF20A as a Target for Inhibitor Development and Immunotherapy

Abstract

The analysis begins with a detailed examination of the gene expression and protein structure of KIF20A, highlighting its interaction with critical cellular components that influence key processes such as Golgi membrane transport and mitotic spindle assembly. The primary focus is on the development of specific KIF20A inhibitors, detailing their roles and the challenges encountered in enhancing their efficacy, such as achieving specificity, overcoming tumor resistance, and optimizing delivery systems. Additionally, it delves into the prognostic value of KIF20A across multiple cancer types, emphasizing its role as a novel tumor-associated antigen, which lays the groundwork for the development of targeted peptide vaccines. The therapeutic efficacy of these vaccines as demonstrated in recent clinical trials is discussed. Future directions are proposed, including the integration of precision medicine strategies to personalize treatments and the use of combination therapies to improve outcomes. By concentrating on the significant potential of KIF20A as both a direct target for inhibitors and an antigen in cancer vaccines, this review sets a foundation for future research aimed at harnessing KIF20A for effective cancer treatment.

Keywords: KIF20A; cancer; inhibitor; peptide vaccine.

Figure 1

Regulation and Functional Architecture of KIF20A. At the chromosomal level, KIF20A is localized on chromosome 5 at q31.2. Regulatory elements such as Gli2 and FOXM1 are depicted; these factors enhance transcriptional activity at the promoter region through interactions with the forkhead responsive element (FHRE). Environmental factors such as lactate are shown modulating gene expression by influencing transcription factors, including E2F. The resultant KIF20A mRNA is processed within the nucleus and subsequently transported into the cytoplasm for translation. In the cytoplasm, the KIF20A mRNA is translated into the protein, which then folds into its active form. The 3D structure of the KIF20A protein is segmented into three distinct domains: the N-terminal motor domain, the central helical domain, and the C-terminal domain. The nucleotide-binding site (NBS), crucial for the protein’s ATPase activity, is prominently marked within the motor domain. Additionally, the loop L6, which is considerably longer than comparable loops in other kinesins, is accentuated to underscore its structural and functional importance. Cartoon in Figure 1 was created with https://BioRender.com and accessed on 1 April 2024.

Figure 2

Biological functions of KIF20A. (A) Golgi vesicle transport: KIF20A mediates the transport of vesicles from the Golgi apparatus towards the extracellular matrix (ECM) via microtubules. The main panel shows the Golgi apparatus with KIF20A guiding RAB6-positive vesicles along microtubules towards their destinations within the cell. Inset diagrams highlight the molecular interactions critical for this process: one shows the N-terminal motor domain of KIF20A interacting with tubulin, which is essential for vesicle propulsion along microtubules; the other depicts the central helical domain of KIF20A in complex with RAB6, demonstrating the specific binding that facilitates precise vesicle routing. (B) PLK1 recruitment: The phosphorylation of KIF20A by PLK1 is shown, which is essential for the recruitment of PLK1 to the central spindle during mitosis, facilitating proper chromosome segregation. (C) CPC-mediated cytokinesis: In late anaphase/telophase, KIF20A is shown interacting with the CPC at the central spindle, which is critical for the completion of cytokinesis and the physical separation of the daughter cells. (D) Activation of the JAK/STAT3 pathway: The illustration depicts the role of KIF20A in activating the JAK/STAT3 pathway. The phosphorylation of STAT3 leads to its dimerization, translocation to the nucleus, and the transcription of genes that contribute to the development of drug resistance. Cartoon in Figure 2 was created with https://BioRender.com and accessed on 3 April 2024.

Figure 3

Comparative Docking Analysis of ATP, Paprotrain, and Compound 9a on the N-terminal Motor Domain of KIF20A. (A) Illustration of ATP (red spheres) bound to the N-terminal motor domain of KIF20A, highlighting the key residues involved in the binding interaction. The inset provides a closer view of the ATP binding site, showing interactions with surrounding amino acids. (B) Visualization of Paprotrain (cyan sticks) within the binding cavity of the KIF20A motor domain. The inset zooms into the interaction details, depicting how Paprotrain aligns and forms contacts with critical residues such as Tyr339, Pro338, and Arg474. (C) Display of Compound 9a (orange sticks) docked at the motor domain of KIF20A. The inset focuses on the binding interactions of Compound 9a, showcasing its engagement with residues like Glu306 and Tyr313, and the expanded binding cavity compared to Paprotrain. The blue lines in the attached file are used to highlight specific regions within the 3D structures of the N-terminal motor domain of the KIF20A protein. These lines connect the overall structure on the left side of each subfigure (A–C) to a zoomed-in view on the right, which details the interactions between the KIF20A protein and the compounds ATP, Paprotrain, and Compound 9a. (D) Table summarizing the Vina docking scores, cavity sizes, center coordinates, and dimensions for ATP, Paprotrain, and Compound 9a. This table provides a quantitative comparison of how each compound interacts with the motor domain of KIF20A, underscoring differences in binding affinity and cavity adaptation. The docking analysis was conducted using CB-Dock, and the downloaded data were modified on https://BioRender.com and accessed on 10 April 2024.

Figure 4

KIF20A Peptide-Driven Immune Activation: Pathways to Cancer Vaccine Development. The expanded diagram would elaborate on the immune response mechanism initiated by KIF20A peptides, starting from the moment the peptides are introduced into the body. It would trace the journey of these peptides as they are ingested by dendritic cells, highlighting the cells’ migration to the lymph nodes. HLA-A24 (A*24:02) binds to MHC class I and activates CD8+ T cells. The * symbol separates the gene locus from the allele designation. In the diagram at the top of the image, the red carboxyl group and the blue amino group represent the key functional groups interacting with HLA-A24 (A*24:02). Although it is not shown in the figure, KIF20A-LP binds to both MHC class I and II, thereby activating both CD4+ T cells and CD8+ T cells. Activated CD8+ T cells recognize and bind to cancer cells presenting the KIF20A antigen. This interaction triggers the release of cytotoxic granules containing perforin, granzyme, and serglycin, leading to the targeted apoptosis of the cancer cells. Cartoon in Figure 4 was created with https://BioRender.com and accessed on 18 April 2024.