Aurora Kinases in HPV-Driven Cancers: Molecular Mechanisms, Oncogenic Footprint, and Therapeutic Vulnerabilities

Martin et al. (2017) assessed the relative contributions of AURKA versus AURKB inhibition in HPV-transformed cells, finding a stronger effect with AURKB inhibition in terms of cell viability and mitotic disruption (77). Sheikh et al. (2018) investigated the therapeutic vulnerability of HPV-positive head and neck cancers (HNCs) by targeting the HPV oncogene E7 and Aurora kinases. The study demonstrated that continuous expression of E7 is essential for the survival of HPV-positive HNC cells. RNA interference–mediated silencing of E7 and pharmacological inhibition of Aurora kinases using Alisertib significantly reduced cell viability and tumor growth in vitro and in vivo . Furthermore, Aurora kinase inhibition led to degradation of the anti-apoptotic protein MCL-1 in E7-expressing cells (102). These findings highlight Aurora kinases as promising therapeutic targets for HPV-driven HNCs, and similar mechanisms could be explored in HPV-associated cervical cancer (CC), where E7-mediated oncogenic pathways play a central role. The precise sequence determinants governing E6-AURKB binding, the full range of AURKB substrates in HPV-infected cells, and the interplay between AURKB and other mitotic kinases, AURKA, polo-like kinase (PLK1), and monopolar spindle (MPS) under the influence of viral oncogenes remain poorly understood and have not been extensively investigated (15). While AURKB overexpression correlates with higher-grade cancers and poor outcomes in some HPV-associated tumors, the clinical biomarker role of AURKB in CC remains under addressed.

Overall, the molecular interplay between high-risk HPV oncoproteins and AURKB shows how viral infection hijacks host mitotic control to drive cervical carcinogenesis. HPV E6 binds and stabilizes AURKB, enhancing its kinase activity, while E6 and E7 disrupt cell polarity and junctional integrity, creating conditions for aberrant mitosis. The resulting AURKB overactivation promotes chromosomal mis-segregation, aneuploidy, telomerase activation, and genomic instability, ultimately supporting uncontrolled proliferation and malignant transformation. This mechanistic dependency highlights AURKB as a potential therapeutic target in HPV-associated CC, encouraging the development of targeted strategies that integrate viral status and kinase profiling for improved clinical outcomes.

Aurora kinase dysregulation is a recurrent feature of human malignancies, linking defective mitotic control to chromosomal instability, adaptation to genotoxic stress, and therapeutic resistance (66). AURKA and AURKB perform nonredundant, stage-specific roles during mitosis: whereas AURKA governs centrosome maturation, spindle assembly and bipolarity, AURKB monitors kinetochore–microtubule attachments, enforces the spindle assembly checkpoint, and directs cytokinesis. Disturbances in either node therefore perturb chromosome segregation fidelity and can drive aneuploidy, tetraploidization, and the micronucleation that fuels genome rearrangement and intra-tumoral heterogeneity (103).

Overexpression or hyperactivation of Aurora kinases is observed across a broad spectrum of cancers, including lung, breast, colorectal, ovarian, and cervical carcinomas, where increased AURKA and AURKB expression has been repeatedly documented in pre-neoplastic lesions and invasive tumors (66). Immunohistochemical (IHC) and transcriptomic analyses indicate that upregulation of AURKA is a relatively early event in malignant transformation of the cervical epithelium and is particularly prominent in squamous histology, correlating with higher stage and poorer outcome in several cohorts (57). AURKB overexpression similarly associates with markers of aggressive biology and worse prognosis in multiple tumor types, supporting both kinases as candidate prognostic biomarkers and potential therapeutic targets.

Mechanistically, Aurora kinase overexpression promotes genomic instability through several interlinked processes. Excess AURKA perturbs cytokinesis and promotes centrosome amplification, leading to tetraploidization. Persistent tetraploidy provides a substrate for subsequent chromosomal missegregation and accumulation of structural variants (104). Overactive AURKB alters kinetochore tension sensing and error correction, precipitating lagging chromosomes and micronucleus formation that seed chromothripsis and complex rearrangements. Experimental ablation of AURKB or pharmacologic inhibition produces characteristic phenotypes loss of phosphorylated histone H3 (a proximate AURKB substrate), premature checkpoint silencing, failed cytokinesis, and polyploidy, underscoring the tight link between Aurora dysfunction and mitotic catastrophe (105).

Beyond these canonical mitotic roles, studies reveal non-mitotic functions for Aurora kinases that broaden their oncogenic footprint. AURKA and AURKB have been implicated in the regulation of the DNA damage response, transcriptional programs, mitochondrial dynamics, and signaling pathways that control survival and invasion (106). AURKA has been reported to interact with and suppress p53 function, to activate NF-κB and Wnt/β-catenin pathways, and to modulate telomerase activity, thereby facilitating both proliferation and evasion of apoptosis (107). These non-mitotic activities create multiple mechanistic axes through which Aurora dysregulation promotes tumor progression, metastatic competence, and therapy resistance.

Therapeutic resistance emerges as a predictable consequence of Aurora dysregulation. Tumors with elevated Aurora activity often display decreased sensitivity to DNA-damaging agents and microtubule poisons because of altered checkpoint dynamics, which permit transient survival despite severe mitotic perturbation (66). Moreover, Aurora overexpression can engage survival signaling, including PI3K/AKT and MAPK pathways, and influence expression of anti-apoptotic BCL-2 family members, thereby inhibiting apoptosis and promoting recovery after cytotoxic damages (108). Functional genomic and pharmacologic studies therefore indicate that monotherapy with Aurora inhibitors frequently yields cytostatic responses or transient regression, with durable responses limited by adaptive rewiring unless orthogonal vulnerabilities such as cell-cycle checkpoint dependence, anti-apoptotic BCL-2 family signaling, PI3K–AKT–mTOR pathway activation, DNA damage response reliance, or spindle assembly checkpoint integrity are simultaneously targeted (109).

The interplay with oncogenic viruses underscores a context in which Aurora kinase dysregulation becomes particularly pathogenic. In HPV-driven cancers, viral oncoproteins E6 and E7 disable p53 and Rb checkpoints and have been reported to modulate Aurora kinase stability and activity (15). Direct biochemical interactions between E6 and AURKB have been described and linked to increased telomerase activity and immortalization phenotypes, providing a mechanistic basis for how viral infection amplifies Aurora-dependent genomic instability and creates selective pressure for Aurora dependency in transformed cells (24). This viral-host interaction suggests that Aurora inhibition may use a virus-specific vulnerability, but it also complicates the prediction of response because post-translational regulation, rather than transcriptional upregulation, often underlies elevated Aurora activity in the HPV context (8).

Genetic screens and RNA interference studies have identified AURKA as a synthetic vulnerability in certain HPV-positive cell lines. These sophisticated experimental approaches, which often rely on advanced cellular analysis techniques , have shown that selective AURKA inhibition can produce tumor regressions in animal models of HPV-transformed disease, indicating potential for a selective therapeutic index in virally driven tumors (78). Conversely, pan-Aurora inhibitors and less selective agents have been constrained clinically by hematologic toxicity and off-target effects, underscoring the need for more selective chemistry, optimized dosing regimens, and rational combination strategies to translate pathway inhibition into meaningful patient benefit (110).