Abstract
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.
Highlights
Chondrosarcomas are malignant cartilage producing tumors and are the third most common bone malignancy [1]
Chondrosarcoma cell lines were variably sensitive to poly(ADP-ribose) polymerase (PARP) inhibition with growth rate corrected IC50 (GR50 ) values ranging from 34 nM to >1000 nM after 72 h of treatment (Figure 1A and Table 1)
Talazoparib inhibited the growth of the cells present before the start of the 72-h drug treatment in most chondrosarcoma cell lines (Figure 1A), cell death in this pre-existing cell population can be induced in almost all chondrosarcoma cell lines at infinite drug concentrations (GRInf values) (Table 1)
Summary
Chondrosarcomas are malignant cartilage producing tumors and are the third most common bone malignancy [1]. Cancers 2019, 11, 1918 have an overall 10-year survival rate of 88%, while patients with a grade II or grade III chondrosarcoma have a reduced survival rate of 62% and 26%, respectively [2]. These survival rates are partly limited by available treatment options, because chondrosarcomas are intrinsically resistant towards conventional chemo- and radiotherapy and targeted therapies are not yet available. Surgery remains the only available curative treatment option [3] These therapeutic limitations emphasize the importance of the development of novel therapeutic strategies, especially for unresectable conventional chondrosarcoma
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