Combination of PARP inhibitor and temozolomide to suppress chordoma progression
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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.
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.
KeywordsChordoma PARP Chemotherapy Olaparib DNA repair
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research (CCR).
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.
- 13.Pang Y, Lu Y, Caisova V, Liu Y, Bullova P, Huynh TT, Zhou Y, Yu D, Frysak Z, Hartmann I, Taïeb D, Pacak K, Yang C (2018) Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma. Clin Cancer Res 24:3423–3432CrossRefGoogle Scholar
- 14.Liu X, Nielsen GP, Rosenberg AE, Waterman PR, Yang W, Choy E, Sassi S, Yang S, Harmon DC, Yang C, Schwab JH, Kobayashi E, Mankin HJ, Xavier R, Weissleder R, Duan Z, Hornicek FJ (2012) Establishment and characterization of a novel chordoma cell line: CH22. J Orthop Res 30:1666–1673CrossRefGoogle Scholar
- 19.Liu Y et al (2019) Targeting IDH1-mutated malignancies with NRF2 blockade. J Natl Cancer InstGoogle Scholar
- 20.Lu Y, Liu Y, Yang C (2017) Evaluating in vitro DNA damage using comet assay. J Vis ExpGoogle Scholar
- 22.N. Kondo, A. Takahashi, K. Ono, T. Ohnishi, DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids 2010, 543531 (2010), 1, 7Google Scholar
- 23.Presneau N, Shalaby A, Ye H, Pillay N, Halai D, Idowu B, Tirabosco R, Whitwell D, Jacques TS, Kindblom LG, Brüderlein S, Möller P, Leithner A, Liegl B, Amary FM, Athanasou NN, Hogendoorn PCW, Mertens F, Szuhai K, Flanagan AM (2011) Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J Pathol 223:327–335CrossRefGoogle Scholar
- 28.Pang Y, Liu Y, Pacak K, Yang C (2019) Pheochromocytomas and paragangliomas: from genetic diversity to targeted therapies. Cancers (Basel) 11Google Scholar
- 31.Ji Y, Vogel RI, Lou E (2016) Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neurooncol Pract 3:188–195Google Scholar
- 33.Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376:245–251CrossRefGoogle Scholar
- 34.Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861CrossRefGoogle Scholar