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Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2

Oncogene volume 37, pages 52–62 (2018)Cite this article

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Abstract

Taxane-based radiochemotherapy is a central treatment option for various cancer entities in locally advanced stages. The therapeutic synergism of this combined modality approach due to taxane-mediated radiosensitization of cancer cells is well-known. However, the underlying molecular mechanisms remain largely elusive, and mechanism-derived predictive markers of taxane-based radiochemotherapy are currently not available. Here, we show that clinically relevant doses of Paclitaxel, the prototype taxane, stimulate a tripolar mode of mitosis leading to chromosomal missegregation and aneuploidization rather than interfering with cell cycle progression. This distinct mitotic phenotype was interlinked with Paclitaxel-mediated radiosensitization via overexpression of mitotic Aurora kinase A (AURKA) and its cofactor TPX2 whose knockdown rescued the bipolar mode of cell division and largely attenuated the radiosensitizing effects of Paclitaxel. In the cancer genome atlas (TCGA) lung adenocarcinoma cohort, high expression levels of AURKA and TPX2 were associated with specifically improved overall survival upon taxane-based radiochemotherapy, but not in case of non-taxane-based radiochemotherapy, chemo- or radiotherapy only. Thus, our data provide insights into Paclitaxel-mediated radiosensitization on a mechanistic and molecular level and identify AURKA and TPX2 as the first potential mechanism-based, predictive markers of taxane-based radiochemotherapy.

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Acknowledgements

We thank Olaf Stemmann for the stably transfected HeLa cell line and the centrin antibody, and Oliver J. Gruss for TPX2 antisera. This work was supported by grants of the Friedrich-Baur-Stiftung and the Verein zur Förderung von Wissenschaft und Forschung to MO and CB.

Author contributions

Conception and design: M. Orth, K. Lauber; Development of methodology: M. Orth, K. Unger, K. Lauber; Acquisition of data: M. Orth, K. Unger, U. Schoetz, K. Lauber; Analysis and interpretation of data: M. Orth, K. Unger, U. Schoetz, K. Lauber; Writing and revision of manuscript: M. Orth, K. Unger, U. Schoetz, C. Belka, K. Lauber.

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Authors and Affiliations

  1. Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany

    M Orth, U Schoetz, C Belka & K Lauber

  2. Clinical Cooperation Group ‘Personalized Radiotherapy in Head and Neck Cancer’ Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany

    M Orth, K Unger, U Schoetz, C Belka & K Lauber

  3. German Cancer Consortium (DKTK), Munich, Germany

    M Orth, C Belka & K Lauber

  4. German Cancer Research Center (DKFZ), Heidelberg, Germany

    M Orth

  5. Research Unit of Radiation Cytogenetics, Helmholtz Center Munich, Neuherberg, Germany

    K Unger

  6. German Center for Lung Research (DZL), Munich, Germany

    C Belka

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Correspondence to K Lauber.

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Orth, M., Unger, K., Schoetz, U. et al. Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2. Oncogene 37, 52–62 (2018). https://doi.org/10.1038/onc.2017.304

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