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Combination of PARP inhibitor and temozolomide to suppress chordoma progression

  • Xiaoyu Cao
  • Yanxin Lu
  • Yang Liu
  • Yiqiang Zhou
  • Hua Song
  • Wei Zhang
  • Dionne Davis
  • Jing Cui
  • Shuyu Hao
  • Jinkyu Jung
  • Qixin Wu
  • Deric M. ParkEmail author
  • Chunzhang YangEmail author
Original Article
  • 51 Downloads

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.

Keywords

Chordoma PARP Chemotherapy Olaparib DNA repair 

Notes

Acknowledgments

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

Author 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

109_2019_1802_MOESM1_ESM.docx (387 kb)
ESM 1 (DOCX 385 kb)
109_2019_1802_MOESM2_ESM.xlsx (16 kb)
ESM 2 (XLSX 15 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Neuro-Oncology Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA
  3. 3.Basic Medical Science DepartmentZunyi Medical College-Zhuhai CampusZhuhaiPeople’s Republic of China
  4. 4.Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People’s HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhenChina
  5. 5.Department of Neurology and the Committee on Clinical Pharmacology and PharmacogenomicsThe University of ChicagoChicagoUSA

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