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Open AccessArticle

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

1
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
2
Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
3
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(12), 1918; https://doi.org/10.3390/cancers11121918
Received: 28 October 2019 / Revised: 21 November 2019 / Accepted: 27 November 2019 / Published: 2 December 2019
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma. View Full-Text
Keywords: sarcoma; chondrosarcoma; isocitrate dehydrogenase; D-2-hydroxyglutarate; AGI-5198; talazoparib; temozolomide; radiotherapy sarcoma; chondrosarcoma; isocitrate dehydrogenase; D-2-hydroxyglutarate; AGI-5198; talazoparib; temozolomide; radiotherapy
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Venneker, S.; Kruisselbrink, A.B.; Briaire-de Bruijn, I.H.; de Jong, Y.; van Wijnen, A.J.; Danen, E.H.; Bovée, J.V. Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status. Cancers 2019, 11, 1918.

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