Targeting Aurora Kinase B (AURKB) in Cancer: Mechanisms, Resistance, and Therapeutic Strategies

The studies to date, therefore, support pairing Aurora Kinase Inhibitors (AKIs) with agents that abrogate compensatory survival, with DNA damage response inhibitors (PARP, CHK1/ATR, or WEE1), or with immunotherapeutic approaches rather than reliance on single-agent activity.

Overall, Aurora kinases present both promise and challenges as therapeutic targets. Their essential role in mitosis makes them attractive for inducing mitotic failure in cancer cells. However, because Aurora kinases are also active in normal proliferating tissues, effective treatment strategies must improve the therapeutic window through isoform-selective inhibitors, tumor-targeted delivery, and rational drug combinations that allow lower and less toxic dosing. In addition, since Aurora kinase dysregulation contributes to genomic instability, inhibition may temporarily limit tumor evolution but also promote the emergence of alternative mitotic adaptation mechanisms. Continuous monitoring of tumor clonal dynamics during therapy will therefore be important to detect and manage resistance early. Further progress in targeting Aurora kinases will depend on integrating fundamental mechanistic insights with well-designed translational trials that incorporate functional biomarkers, adaptive treatment strategies, and biologically informed combination therapies. This approach provides a rational path to effectively exploit Aurora kinase dysregulation across multiple cancer types, including cervical carcinoma. The mechanistic basis for these strategies, along with representative examples of Aurora kinase alterations in cancer, is supported by key foundational reviews and primary studies. Understanding the structural basis of these interactions is crucial, and resources like RCSB PDB entry 1I3O provide valuable insights.

AURKB maintains genomic stability in normal cells by regulating chromosome condensation, correcting erroneous kinetochore-microtubule attachments, securing proper chromosome alignment, and activating the spindle assembly checkpoint (SAC) to prevent missegregation. Together with its CPC partners, AURKB localizes first to chromosome arms, then centromeres, and finally the central spindle and midbody as mitosis proceeds. When chromosomes are not properly attached, AURKB destabilizes these connections by phosphorylating multiple substrates, permitting corrective realignment to facilitate accurate segregation. AURKB also plays a vital role in cytokinesis, where the loss or inhibition of AURKB results in failed cytokinesis and promotes the formation of polyploid, genomically unstable cells. Dysregulation of AURKB, in HPV-driven malignancies, contributes significantly to tumorigenesis. In cervical carcinoma (CC), AURKB overexpression is observed in 40-60% of HPV-positive tumors, contributing to chromosomal instability and increased tumor aggressiveness. The HPV E6 oncoprotein can interact directly with AURKB in the nucleus of mitotic cells, promoting E6-AURKB complex formation. This molecular interaction paradoxically reduces AURKB kinase activity but increases hTERT protein and telomerase activity, facilitating cell immortalization.

One of the key molecular functions of AURKB is the regulation of chromosome microtubule attachments. During prometaphase and metaphase, AURKB localizes to centromeres, where it is ideally positioned to monitor and correct erroneous kinetochore-microtubule attachments. AURKB achieves this by phosphorylating various kinetochore and centromere proteins, including Hec1, Dsn1, and the Ndc80 complex, thereby destabilizing improper attachments. This phosphorylation activity leads to the establishment of proper amphitelic attachments, where each chromosome is attached to spindle poles from opposite sides.

AURKB is also known to be a principal regulator of the spindle assembly checkpoint (SAC). The SAC ensures that cells do not proceed to anaphase until all chromosomes have attained proper alignment at the metaphase plate and stable bipolar attachments. AURKB regulates SAC activation both by generating tension at correctly attached kinetochores and by sustaining the accumulation of checkpoint proteins such as BUBR1, MAD2, and Mps1 at unattached kinetochores. Inhibition or loss of AURKB leads to rapid checkpoint silencing, premature anaphase onset, chromosomal mis-segregation, and the generation of micronuclei in daughter cells, all of which contribute to genome instability.

Another crucial phase of mitosis regulated by AURKB is cytokinesis, where, during anaphase and telophase, together with the rest of the CPC, it translocates to the central spindle. AURKB is shown to promote the assembly and constriction of the actomyosin, coordinates the reorganization of the central spindle microtubules, and directly regulates proteins such as MKLP1 and CIT-K. Misregulated AURKB activity impairs the cytokinetic abscission process, resulting in the generation of multinucleated or polyploid cells. This mitotic failure induces persistent chromosomal instability, which promotes aggressive tumorigenesis through the accumulation of genetic aberrations.

Upregulation of AURKB in HPV-positive cancers is primarily regulated post-transcriptionally and involves direct interactions between AURKB and viral oncoproteins. It has been shown that E6 from high-risk HPV can physically interact with AURKB in the nucleus of mitotic cells, forming a complex with yet unclear molecular effects. Although this complex is associated with reduced AURKB kinase activity, it correlates with elevated telomerase (hTERT) and increased cell immortalization, providing a mechanism for the oncogenic synergy between HPV infection and host mitotic kinases. High-risk HPV types influence the degradation of tumor suppressors such as p53 and pRb via E6 and E7, respectively, further enhancing the tolerance for chromosomal instability introduced by AURKB overexpression or hyperactivation.

Despite the preclinical activity, resistance to AURKB-targeted therapy remains a major challenge that limits durable therapeutic responses. Similar to other mitotic kinase inhibitors, tumor cells may acquire adaptive mechanisms that bypass mitotic stress and restore proliferative capacity. One such mechanism involves activation of parallel survival signaling pathways, including PI3K/AKT/mTOR and MAPK/ERK cascades, which promote cellular survival despite mitotic disruption induced by AURKB inhibition. Upregulation of anti-apoptotic proteins such as BCL-2, BCL-XL, and MCL-1 may further reduce treatment-induced apoptosis, contributing to resistance development.

Alterations in cell-cycle checkpoint regulators are shown to influence sensitivity to AURKB inhibitors. It is known that small-cell lung cancer cells harboring defective p53 or pRb pathways frequently exhibit increased dependency on mitotic regulators and enhanced susceptibility to AURKB inhibition. Given that CC commonly exhibits dysregulation of p53 and pRb signaling, particularly in HPV-associated disease, a similar vulnerability to AURKB inhibition may potentially exist in CC cells. However, prolonged therapeutic exposure can promote adaptive rewiring of spindle assembly checkpoint (SAC) signaling, DNA damage response pathways involving ATR, CHK1, and WEE1, and compensatory mitotic kinase activity mediated by AURKA, polo-like kinase 1 (PLK1), and monopolar spindle kinase 1 (MPS1), thereby restoring mitotic progression and cellular survival. Functional redundancy among mitotic kinases represents an important mechanism of resistance in tumors exposed to prolonged Aurora kinase inhibition. For more information on structural biology databases, PDBj is a valuable resource.

Emerging evidence further suggests that genomic and molecular biomarkers may improve patient stratification for AURKB-targeted therapy. Elevated AURKB expression, HPV-positive molecular status, phospho-AURKB abundance, spindle checkpoint dependency, and defects in p53 and pRb signaling may predict improved therapeutic responsiveness. In contrast, activation of PI3K/AKT signaling, elevated anti-apoptotic protein expression, and enhanced DNA damage repair capacity may identify tumors less likely to respond to monotherapy approaches.