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Combination of PARP inhibitor and temozolomide to suppress chordoma progression

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Abstract

Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifested as lack of DNA damage accumulation. Mechanistically, the PARP DNA repair pathway was found to play a central role in this resistance. Chemical screening confirmed that PARP inhibitors could strikingly enhance temozolomide (TMZ) therapy in chordoma cells. Combining the FDA-approved PARP inhibitor, olaparib, with chemotherapeutics not only potentiated DNA damage accumulation, cell cycle arrest, and apoptosis in vitro but also suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibition with TMZ could be an effective therapeutic approach for the clinical management of chordoma.

Key messages

  • The PARP DNA repair pathway enhances chemoresistance in chordoma cells.

  • Combining PARP inhibitors with genotoxic agents induces chordoma cell cytotoxicity.

  • PARP inhibitor combining with temozolomide suppresses growth of chordoma in vivo.

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Acknowledgments

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR).

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Author notes

  1. Xiaoyu Cao, Yanxin Lu, and Yang Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China

    Xiaoyu Cao & Shuyu Hao

  2. Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 1142E, Bethesda, MD, 20892, USA

    Xiaoyu Cao, Yanxin Lu, Yang Liu, Yiqiang Zhou, Hua Song, Wei Zhang, Dionne Davis, Jing Cui, Jinkyu Jung, Qixin Wu, Deric M. Park & Chunzhang Yang

  3. Basic Medical Science Department, Zunyi Medical College-Zhuhai Campus, Zhuhai, Guangdong, 519041, People’s Republic of China

    Yanxin Lu

  4. Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, Guangdong, China

    Yanxin Lu

  5. Department of Neurology and the Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, 60637, USA

    Deric M. Park

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  1. Xiaoyu Cao
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Contributions

XC, YL, and YL designed and performed the study, analyzed the data, and drafted the manuscript. HS, WZ, and DD performed the study and analyzed the data. YZ, JC, SH, JJ, and QW analyzed the data. Corresponding authors DMP and CY contributed to the conceptual design of the study, interpreted the data, and critically revised the manuscript. All authors have given final approval and agree to be accountable for all aspects of the work.

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Correspondence to Deric M. Park or Chunzhang Yang.

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Cao, X., Lu, Y., Liu, Y. et al. Combination of PARP inhibitor and temozolomide to suppress chordoma progression. J Mol Med 97, 1183–1193 (2019). https://doi.org/10.1007/s00109-019-01802-z

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