Aurora Kinase B: A Pivotal Oncogenic Driver and Therapeutic Target in HPV-Associated Cancers

Depletion of HPV E6 and E7 leads to marked reductions in both total and phosphorylated AURKB protein without significant changes at the RNA level, highlighting a layer of viral-mediated post-translational regulation (24). E6 is known to trigger ubiquitin-mediated destruction of p53, thereby disabling the DNA damage response, while E7 binds and inactivates Rb, liberating E2F target genes and promoting G1/S cell cycle transition (159, 160). The effect is a loss of mitotic checkpoint control, a condition that greatly amplifies the consequences of AURKB overexpression, as cells become increasingly tolerant of chromosome missegregation and polyploidy (121).

Cell proliferation in HPV-driven cancers is due to hyperactivation and stabilization of AURK, and also deactivation of p53 and Rb. This molecular environment accelerates the cell cycle, limits apoptosis, and undermines the genomic stability required for normal tissue homeostasis (102). AURKB is known to phosphorylate p53 at Ser315, marking it for proteasomal degradation and further suppressing pro-apoptotic genes such as BAX and BAD (66). Additionally, AURKB supports STAT3 phosphorylation at Ser727, thereby enhancing transcription of anti-apoptotic genes and increasing cancer cell survival (66).

The pro-metastatic potential of AURKB is also underscored by its role in epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling. Overexpressed AURKB upregulates the activity of matrix metalloproteinases (MMPs), enzymes that enable cancer cells to degrade surrounding tissue and invade distant organs (116). Activation of focal adhesion kinase (FAK) and Rho GTPase pathways driven by AURKB further enhances cell migration and motility, promoting metastatic progression (66). In CC models and other HPV-related tumors, AURKB silencing or inhibition results in potent anti-proliferative effects, restoration of apoptotic pathways, impaired EMT, reduced motility, and loss of metastatic potential (27).

Collectively, these findings establish that AURKB acts as a central molecule for crosstalk with HPV oncogenic pathways in CC. The synergistic disruption of cell cycle checkpoints, mitotic surveillance, and apoptotic programs by the combined action of HPV oncoproteins and AURKB overexpression accelerates malignant transformation, supports cell survival under stress, and enables dissemination.

Combination therapies involving aurora kinase inhibitors represent a rapidly evolving strategy in the management of CC, particularly for tumors associated with HPV infection (161). The therapeutic targeting of AURKA and AURKB has thus emerged as a rational approach, with growing preclinical and clinical evidence supporting the enhanced efficacy of combination regimens over monotherapy. For a deeper understanding of the Aurora Kinase family pharmacology , refer to specialized resources. Preclinical investigations have demonstrated that aurora kinase inhibitors, such as MLN8237 (Alisertib) and AZD1152-hQPA (Barasertib), exhibit potent anti-proliferative effects in CC cell lines (139). Zhang et al., 2011 investigated the role of AURKB in CC and the effects of its inhibition with ZM447439, alone and in combination with Cisplatin. The study found that AURKB was highly expressed in CC tissues and that its inhibition suppressed cell growth and induced apoptosis. Combined treatment with ZM447439 and Cisplatin produced a stronger inhibitory and apoptotic effect than either drug alone, suggesting a synergistic interaction. The dual treatment also reduced the expression of oncogenic and anti-apoptotic proteins while increasing P53 levels. Overall, the findings indicate that targeting AURKB may enhance the sensitivity of CC cells to chemotherapy and serve as a potential therapeutic approach (23). Sootome et al., 2020 demonstrated that TAS-119, a novel oral and selective AURKA inhibitor, enhanced the antitumor efficacy of taxanes such as paclitaxel and docetaxel. TAS-119 increased the growth-inhibitory effects of taxanes, including resistant ones, without affecting normal cells. In CC animal models, the combination improved antitumor activity without worsening taxane-associated toxicities like neutropenia or neurotoxicity. These findings highlighted TAS-119 as a promising agent for combination therapy with taxanes (162).

Dual inhibition of aurora kinases and anti-apoptotic BCL-2 family members produced rapid and enhanced cell death in CC cell lines. Alisertib combined with small-molecule antagonists of BCL-2, BCL-XL, or MCL-1, caused apoptosis during mitotic delay. These findings identified that aurora kinase inhibitors-induced mitotic stress created a dependence on anti-apoptotic proteins that could be therapeutically exploited (139).

Inhibition of stress-activated kinases has been demonstrated to potentiate the therapeutic efficacy of aurora kinase inhibition in CC models. Specifically, pharmacologic blockade of p38 MAPK using BIRB796 has been shown to enhance the antitumor activity of the pan-Aurora kinase inhibitor VX-680 (MK-0457) in CC cells. The combined treatment produced tumor growth suppression compared with either agent alone, both in vitro and in xenograft models. Mechanistically, activation of the p38 MAPK pathway following mitotic disruption facilitated cellular survival and recovery from mitotic stress. Consequently, concurrent inhibition of p38 MAPK abrogated this adaptive response, thereby amplifying apoptosis and mitotic arrest induced by aurora kinase inhibition. This dual-targeting approach effectively disabled compensatory stress-response signaling, providing a strategy to enhance the cytotoxic potential of aurora kinase inhibitors in CC (163).

Zhang et al., 2011 investigated the role of AURKB in CC and determined how its inhibition with ZM447439 affects SiHa cells, both alone and in combination with cisplatin. They found that AURKB is highly expressed in CC tissues and that blocking its activity reduces cell growth and promotes apoptosis. ZM447439 and cisplatin each suppressed cell proliferation, but their combination produced a much stronger, synergistic effect, leading to enhanced S-phase arrest and early apoptosis. The dual treatment more effectively decreased HPV16E6 and BCL-2 while increasing P53 expression, suggesting a stronger pro-apoptotic response (23). Overall, AURKB was suggested to be a promising therapeutic target in cervical squamous carcinoma and that its inhibition can enhance the chemosensitivity of CC cells to cisplatin.

Jin et al., 2016 examined the effects of the Aurora kinase inhibitor VX-680 on CC cells and explored whether blocking p38 MAPK could enhance its pro-apoptotic activity. They observed that VX-680 inhibited CC cell proliferation by inducing G2/M arrest, but activation of p38 MAPK reduced apoptosis. Inhibiting p38 MAPK with BIRB796 eliminated p-p38 signaling and increased VX680-induced cell death. The combination also showed stronger tumor suppression in a mouse xenograft model (163). Overall, the study suggested that dual inhibition of Aurora kinases and p38 MAPK produced synergistic antitumor effects and represents a promising therapeutic strategy for CC.

Martin et al., 2017 demonstrated that Alisertib, although primarily considered an AURKA inhibitor, effectively inhibits both AURKA and AURKB in preclinical models of HPV-driven CC. Their findings show that dual inhibition of these kinases is essential for the drug’s selectivity and antitumor efficacy. They also showed that Alisertib relies on cells progressing through mitosis to exert its therapeutic effects and is therefore unlikely to interact with agents that enforce a G2 DNA-damage checkpoint (77). Overall, the study highlights that simultaneous targeting of AURKA and AURKB is necessary for effective treatment of HPV-driven cancers using Aurora kinase inhibitors. For a broader perspective on current advances in clinical cancer research , further reading from leading journals is recommended. The principal preclinical combination studies and selected clinical combination trials in CC are provided in the Table below.

Table 1: Key Preclinical and Clinical Combination Studies Targeting Aurora Kinases in Cervical Cancer (CC)

Together, these studies have demonstrated the wide range of promising combination strategies involving aurora kinase inhibitors, and underscore the need for CC focused clinical testing that incorporates biomarker-guided patient selection and optimized dosing schedules.