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 termwith an inhibitor normalizing
D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib
Show moreChondrosarcomas 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 termwith 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, andO-6-methylguanine-DNAmethyltransferase (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.
Show less
