Aurora kinases signaling in cancer: from molecular perception to targeted therapies

Abstract

Aurora kinases, AURKA, AURKB, and AURKC, are serine/threonine kinases that play a vital role in regulating cell division and mitosis, particularly in the separation of chromosomes. These kinases are often overexpressed in human tumor cell lines, indicating their potential involvement in tumorigenesis. Preliminary evidence supports the use of Aurora kinase inhibitors for certain types of tumors, several AURKs inhibitors are currently under phase I and II trials. As a result, there is a growing interest in identifying small-molecule Aurora kinase inhibitors to develop as anti-cancer agents. The regulation of the cell cycle, including mitosis, is increasingly recognized as a key target in the fight against various forms of cancer. Novel drugs are being designed to inhibit the function of regulatory proteins, such as Aurora kinases, with the goal of creating personalized treatments. This review summarizes the biology of Aurora kinases in the context of cancer, integrating both preclinical and clinical data. It discusses the challenges and opportunities associated with using Aurora kinases to enhance cancer treatment. Future directions for Aurora kinase-based therapies include developing more selective inhibitors that minimize off-target effects and improve therapeutic efficacy. Researchers are also exploring combination therapies that use Aurora kinase inhibitors alongside other targeted treatments to overcome resistance and improve patient outcomes. Additionally, advancements in biomarker discovery are expected to facilitate the identification of patients most likely to benefit from Aurora kinase-targeted therapies, paving the way for more personalized approaches to cancer treatment.

Keywords: AKIs; AURKA; AURKB; AURKC; Cancer Diagnosis and Prognosis; Targeted Therapy.

Fig. 1

The evolutionary relationship between Aurora kinases highlights their conserved roles in cell cycle regulation across species. The phylogenetic relationships among these kinases across various species shows structural similarities, including key functional regions like kinase domains, phosphorylation sites, and regulatory motifs. The evolutionary divergence of these kinases suggests functional adaptations, with some species retaining conserved sequences while others exhibit modifications. This evolutionary perspective provides insights into how Aurora kinases have developed specialized roles in cellular processes

Fig. 2

This figure illustrates the roles of Aurora Kinases A and B in mitosis, highlighting their interactions with various regulatory proteins. In panel A, Aurora Kinase A is shown in early mitotic events, such as centrosome maturation, microtubule remodeling, and bipolar spindle formation. It interacts with key regulators like PLK1, CDC25B, TPX2, and MAP215, ensuring proper spindle assembly and chromosome alignment. In panel B, Aurora Kinase B is depicted as a crucial player in chromosome segregation and cytokinesis. It is part of the chromosomal passenger complex (CPC), which includes INCENP, Survivin, and Borealin, facilitating error correction in kinetochore-microtubule attachments and activating the spindle checkpoint. Aurora Kinase B also regulates chromatin remodeling via Histone H3 phosphorylation and participates in central spindle assembly and cleavage furrow ingression during cytokinesis

Fig. 3

Role of Aurora Kinase A (AURKA) in promoting cell survival and proliferation by modulating key signaling pathways. AURKA interacts with and phosphorylates p53 at Ser315, leading to its degradation and inhibition of apoptosis. Additionally, AURKA activates the NF-κB pathway, increasing the expression of anti-apoptotic proteins such as Bcl-XL and Survivin, further promoting cell survival. Another critical pathway influenced by AURKA is the PI3K/Akt signaling cascade, which is activated through Akt phosphorylation. This activation leads to the transcription of oncogenic genes like C-Myc, VEGF, CCND1, and CLDN1, driving uncontrolled cell proliferation. The presence of PI3K inhibitors can potentially block this pathway, reducing proliferation. Overall, AURKA functions as an oncogenic kinase by suppressing apoptosis and enhancing cell survival, making it a key target in cancer research and therapy

Fig. 4

The role of Aurora Kinase A and Aurora Kinase B in cancer cell invasion and motility. Both kinases contribute to tumor progression through different pathways. Aurora Kinase A enhances the activity of matrix metalloproteinases (MMPs), which leads to extracellular matrix (ECM) degradation, a critical step in cancer cell invasion. Meanwhile, both Aurora Kinase A and B upregulate focal adhesion kinase (FAK), which promotes cell adhesion dynamics, and Rho GTPase signaling, which is involved in cytoskeletal remodeling. The activation of Rho GTPase signaling results in increased cell motility, further facilitating invasion. Together, these pathways contribute to cancer metastasis by enabling tumor cells to degrade surrounding tissue and migrate to new locations

Fig. 5

The roles of Aurora Kinase B and Aurora Kinase C in regulating apoptosis and cell survival through different molecular pathways. Aurora B can induce apoptosis by phosphorylating p53 at Ser315, activating pro-apoptotic proteins like BAX and BAD. However, it also promotes survival by activating STAT3 (Ser727), which drives the expression of anti-apoptotic genes. Aurora Kinase C, on the other hand, promotes cell survival through the PI3K/Akt pathway. It phosphorylates PI3K, leading to the activation of Akt, which in turn phosphorylates MDM2, a negative regulator of p53. Phosphorylated MDM2 promotes p53 degradation, thereby reducing apoptosis. Active p53, transcribes pro-apoptotic genes such as BAX, PUMA, and NOXA, further influencing the balance between cell survival and death. Overall, Aurora Kinases B and C exhibit dual roles in cancer progression by modulating apoptotic and survival pathways, making them significant targets for therapeutic interventions