Aurora Kinase B as a Therapeutic Target in HPV-Induced Cervical Cancer: Mechanisms and Future Perspectives

Aurora kinase B (AURKB) is a core component of the chromosomal passenger complex, which plays a central role in regulating chromosome condensation, spindle checkpoint function, and cytokinesis. Dysregulated AURKB activity leads to chromosomal instability and aneuploidy, which are the key drivers of oncogenesis. In cervical cancer, persistent infection with high-risk human papillomaviruses (HPV16 and HPV18) initiates carcinogenesis through the viral oncoproteins E6 and E7, which disable tumor suppressor pathways. Recent evidence indicates that E6 and E7 also influence AURKB activity, thereby exacerbating genomic instability, overriding cell-cycle checkpoints, and accelerating tumor progression. Overexpression of AURKB has been reported in cervical cancer and correlated with tumor stage, therapeutic resistance, and poor prognosis. Preclinical investigations demonstrate that pharmacological inhibition of AURKB suppresses tumor cell proliferation, induces mitotic catastrophe, and enhances sensitivity to chemotherapy and radiotherapy. Although clinical evaluation of these AURKB inhibitors such as barasertib (AZD1152) and AZD2811 remains limited, early findings support their potential efficacy, particularly in rationally designed combination regimens. This review describes the mechanistic interplay between HPV oncogenes and AURKB, highlights its role as a biomarker of aggressive disease, and critically assesses the therapeutic promise of AURKB inhibition. Finally, we outline future perspectives on integrating AURKB-targeted therapies into precision oncology for HPV-driven cervical cancer.

Cervical Cancer: A Global Health Challenge and the Role of HPV

Cervical cancer (CC) continues to pose a major health burden globally. Ranked as the fourth most common malignancy among women, CC has contributed an estimated 660,000 new cases and 350,000 deaths in the year 2022. The impact of the disease is particularly distressing in low- and middle-income countries (LMICs), where inadequate access to human papillomavirus (HPV) vaccination and limited implementation of effective screening programs contribute to persistent health disparities. Epidemiological projections suggest that in the absence of significant preventive and intervention strategies, the incidence and mortality of CC could rise by approximately 56.8% and 80.7%, respectively, by the year 2050. More than 99% of CC cases are causally linked to persistent infection with high-risk HPV genotypes, most notably HPV16 and HPV18, underscoring the critical importance of vaccination, early detection, and sustained global efforts in prevention and control.

Oncogenic Mechanisms of High-Risk HPV: E6 and E7 oncoproteins

The oncogenic potential of high-risk HPV lies primarily in the expression of viral oncoproteins E6 and E7, which orchestrate cellular transformation through multiple mechanisms beyond the disruption of p53 and retinoblastoma (pRb) tumor suppressor pathways. HPV E6 and E7 engage in more complex interactions with host cellular machinery involving epigenetic reprogramming, metabolic rewiring, immune evasion, and the induction of chromosomal instability. These viral oncoproteins not only disable cell cycle checkpoints but also actively promote DNA damage accumulation, replication stress, and mitotic errors, creating a cellular environment favorable to malignant transformation. Among the 15 recognized high-risk oncogenic HPV types, HPV16 and HPV18 emerged as the predominant drivers, collectively responsible for approximately 70% of CC cases worldwide. HPV16 has aggressive carcinogenic potential compared to other high-risk types, such as HPV58, as it exhibits enhanced ability to drive malignant transformation through more efficient disruption of cellular tumor suppressor pathways. The HPV16 E7 oncoprotein has been shown to degrade the retinoblastoma protein more effectively compared to the HPV58 E7, resulting in enhanced cell proliferation, invasion, and resistance to apoptosis. This differential oncogenic potency among HPV sub-types has important implications in understanding disease progression and developing targeted treatment.

HPV E6 and E7: Disruption of Cellular Pathways and Interaction with Host Proteins

The molecular mechanisms underlying HPV-driven carcinogenesis are propelled by E6 and E7 proteins, which orchestrate cellular transformation through the systematic disruption of host cellular pathways. HPV E6 oncoprotein targets the cellular E3 ubiquitin ligase E6AP (E6-associated protein) to p53, resulting in proteasome-mediated p53 degradation and subsequent loss of cell cycle checkpoint control. Simultaneously, E6 disrupts multiple cellular processes by interacting with over 400 host proteins, including transcription factors (p300/CBP), DNA repair proteins (XRCC1, MGMT), apoptosis regulators (Bak, FADD), and PDZ domain-containing proteins involved in cell polarity and adhesion.

Aurora Kinase B (AURKB): A Key Player in HPV-Driven Carcinogenesis

Among the cellular targets dysregulated by HPV oncoproteins, Aurora kinase B (AURKB) has emerged as an important player in HPV-driven carcinogenesis. AURKB, encoded by the AURKB gene, serves as the enzymatic core of the chromosomal passenger complex (CPC), a multiprotein assembly comprising AURKB, survivin (BIRC5), inner centromere protein (INCENP), and borealin (CDCA8). This complex induces critical mitotic processes, including chromosome condensation, kinetochore assembly, spindle checkpoint function, and cytokinesis completion. Under physiological conditions, AURKB ensures genomic stability by correcting erroneous kinetochore-microtubule attachments and preventing premature anaphase onset until all chromosomes are properly aligned. Studies have revealed that AURKB is frequently overexpressed across multiple cancer types, with particularly elevated levels in CCs. Aurora A (AURKA) is also upregulated in 60-80% of CCs, correlating with increased tumor aggressiveness and poor prognosis. Moreover, emerging evidence indicates direct mechanistic interactions between HPV E6 oncoprotein and AURKB, involving physical binding that modulates AURKB kinase activity and subcellular localization. These interactions appear to enhance the oncogenic potential of both viral and cellular components, creating a synergistic effect that accelerates genomic instability and tumor progression. For a detailed exploration of mitotic regulation, see Nature Methods .

AURKB as a Biomarker and Therapeutic Target in Cervical Cancer

In CC specifically, AURKA overexpression was identified as an independent adverse risk factor for both recurrence-free survival and overall survival in cervical squamous cell carcinoma patients treated with definitive radical radiotherapy. However, AURKB overexpression also serves as a biomarker across multiple malignancies, with significant correlations between elevated expression and reduced survival outcomes established through meta-analytical approaches. These findings from multiple independent cohorts have positioned AURKB not only as a validated prognostic biomarker for risk stratification but also a promising therapeutic target with demonstrated clinical relevance across diverse cancer types.

Mechanisms of AURKB Inhibitor Sensitivity in HPV-Driven Cancers

The mechanistic basis for enhanced AURKB inhibitor sensitivity in HPV-driven cancers relates to the loss of p53 and pRb function mediated by viral E6 and E7 oncoproteins. AURKB inhibition in cells with defective p53 and pRb pathways leads to hyperpolyploidy and subsequent mitotic catastrophe, while normal cells with intact tumor suppressor function can undergo senescence and survive treatment. This differential response could provide a therapeutic aspect for the selective targeting of HPV-transformed cells.

Future Perspectives and Therapeutic Promise

This review discusses current understanding of the mechanistic interplay between HPV oncoproteins E6 and E7 and AURKB in cervical carcinogenesis, evaluates the biomarker potential of AURKB for disease prognosis and therapeutic response prediction. We also assessed the therapeutic promise of AURKB inhibition in both monotherapy and combination settings. We examined recent advances in drug development, including novel formulations and delivery approaches, while addressing the challenges and opportunities for integrating AURKB-targeted therapies into precision oncology.