Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors

Martín, David; Fallaha, Sora; Proctor, Martina; Stevenson, Alexander J.; Perrin, Lewis; McMillan, Nigel A.J.; Gabrielli, Brian

doi:10.1158/1535-7163.mct-17-0159

Cited by 15 publications

(11 citation statements)

References 27 publications

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“…They have each been previously reported to be overexpressed in HPV-positive CIN or cancer and some have been evaluated for use as biomarkers [90] , [91] , [92] . Other genes, such as the genes encoding for aurora kinase A and B (AURKA and AURKB), have been implicated as survival signals for HPV-infected cells and inhibition of AURKA/B using Alisertib induced cell death in HPV-transformed cervical cancer cell lines [93] , [94] . It important to note that the utility of this drug was also evaluated in the K14E7 skin grafting model where Alisertib-treated E7-expressing skin grafts displayed increased apoptotic bodies compared to untreated controls [93] .…”

Section: Resultsmentioning

confidence: 99%

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Tuong

Noske

Kuo

et al. 2018

Papillomavirus Research

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Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines.

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Section: Resultsmentioning

confidence: 99%

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Tuong

Noske

Kuo

et al. 2018

Papillomavirus Research

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“…Alisertib treatment of mice bearing HPV + OPC cells successfully inhibited tumour growth but failed to eliminate tumours completely (6). We consider the possibility that alisertib treatment was not effective at eliminating E7 expressing tumours in vivo despite our previous observations that alisertib-mediated killing of HPV + tumours are sensitized to the presence of E7 (5)(6)(7). Owing to our recent success at completely eliminating HPV + cervical cancer tumours in vivo by deleting E7 using CRISPR technology (10), we rationalize that this would occur in HPV + OPC tumours.…”

Section: Resultsmentioning

confidence: 86%

“…High-risk HPV cancers are driven by major HPV oncogenes, E6 and E7, which promote uncontrolled cell growth and genomic instability by down-regulate the tumour suppressor proteins, p53 and retinoblastoma (Rb), respectively (4). Our lab has shown that the presence of HPV E7 sensitizes both HPV + cervical and HPV + OPC tumours to tumour regression by inhibiting aurora kinases (AURKs) using an investigational AURK inhibitor, alisertib (5)(6)(7). AURKs are a group of serine-threonine kinases that regulate cell cycle and are involved in a variety of processes including centrosome maturation, entry in mitosis, microtubule spindle assembly, and cytokinesis (8-9).…”

Section: Introductionmentioning

confidence: 99%

Genetic deletion of HPV E7 oncogene effectively eliminates HPV driven oropharyngeal cancer tumours

Idris

McMillan

Ferreira³

2022

Preprint

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The major HPV oncogenes E6 and E7 are known for its notoriety in driving the carcinogenic process in human papilloma virus (HPV) driven cancers. It is well-established that the removal of E7 dampens HPV cancer cell growth and proliferation. This has made E7 one of the most attractive targets for HPV cancers. Seminal work from our laboratory employed in vivo CRISPR editing treatment to delete E7, resulting in the effective elimination of HPV positive (HPV+) cervical cancer tumours in vivo. We have also successfully delayed HPV+ tumour growth in vivo with aurora kinase (AURK) inhibitors, an effect which is strongly sensitized by the presence of E7 expression. Unlike our observations in cervical cancer cells, in vitro targeting of E6/E7 have only resulted in partial killing of HPV+ oropharyngeal cancer (OPC) cells. The effect of E7 removal on HPV+ OPC tumours in vivo have not been explored. In this study we investigated a staggered combination of aurora kinase inhibition, using alisertib, followed by CRISPR editing of E7, to determine if this would lead to better HPV+ OPC cell killing in vitro and in vivo. Remarkably, genetic deletion of E7 alone was sufficient to effectively eliminate established HPV+ OPC tumours in vivo suggesting that E7 is essential in the maintenance of HPV+ OPC cancers.

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“…In addition, Aurora A also participates in the regulation of the G2/M phase cell cycle checkpoint; Aurora A overexpression can counter the checkpoint activation induced by DNA damage in the G2/M phase, resulting in genome instability and tumour formation. Increasing evidence has revealed that aberrant Aurora A expression was found in lung adenocarcinoma, liver, colon and breast cancer, and many other malignant tumours (16,17). The overexpression of Figure 5.…”

Section: Discussionmentioning

confidence: 99%

miRNA‑885‑3p inhibits docetaxel chemoresistance in lung adenocarcinoma by downregulating Aurora�A

et al. 2018

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Aurora A is a member of the mitotic serine/threonine kinase family. It is involved in key processes during mitosis and meiosis, and Aurora A upregulation is implicated in malignant transformation. In the present study, we revealed that Aurora A expression was significantly higher in docetaxel-resistant lung adenocarcinoma (LAD) cells than in parental cells. Higher levels of Aurora A expression were significantly correlated with higher chemoresistance and proliferation in LAD cells, while silencing Aurora A promoted caspase-3-dependent cell apoptosis by downregulating NF-κB and Bcl-2 and upregulating Bax expression. In addition, an increased proportion of cells in the G2/M phase and a decreased proportion of cells in the S phase were observed due to the suppression of Aurora A. Furthermore, we identified that microRNA-885-3p (miR-885-3p) could target Aurora A directly. There was significantly lower miR-885-3p expression in docetaxel-resistant LAD cells than in parental LAD cells. miR-885-3p could modulate the docetaxel response, cell proliferation and apoptosis in LAD cells in vitro. Moreover, we found that Aurora A overexpression or miR-885-3p inhibition was associated with more aggressive behaviour in LAD cells. Thus, miR-885-3p/Aurora A may be involved in the chemoresistance of LAD cells, and assessing miR-885-3p/Aurora A expression may be a potential method for indicating chemosensitivity to docetaxel-based chemotherapy.

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Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors

Cited by 15 publications

References 27 publications

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Genetic deletion of HPV E7 oncogene effectively eliminates HPV driven oropharyngeal cancer tumours

miRNA‑885‑3p inhibits docetaxel chemoresistance in lung adenocarcinoma by downregulating Aurora�A

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