Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair
Yanxin Lu, Jakub Kwintkiewicz, Yang Liu, Katherine Tech, Lauren N Frady, Yu-Ting Su, Wendy Bautista, Seog In Moon, Jeffrey MacDonald, Matthew G Ewend, Mark R Gilbert, Chunzhang Yang, Jing Wu, Yanxin Lu, Jakub Kwintkiewicz, Yang Liu, Katherine Tech, Lauren N Frady, Yu-Ting Su, Wendy Bautista, Seog In Moon, Jeffrey MacDonald, Matthew G Ewend, Mark R Gilbert, Chunzhang Yang, Jing Wu
Abstract
Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas. Cancer Res; 77(7); 1709-18. ©2017 AACR.
©2017 American Association for Cancer Research.
Figures
![Figure 1. IDH1 mutant glioma cells are…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5380481/bin/nihms-849346-f0001.jpg)
![Figure 2. Enhanced DNA damage in IDH1…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5380481/bin/nihms-849346-f0002.jpg)
![Figure 3. Metabolic reprogramming results in chemo-sensitivity…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5380481/bin/nihms-849346-f0003.jpg)
Figure 4. Dysfunction of the PARP1 DNA…
Figure 4. Dysfunction of the PARP1 DNA repair pathway in IDH1 mutant cells
A. Immunostaining…
Figure 5. Targeting the PARP DNA repair…
Figure 5. Targeting the PARP DNA repair pathway enhanced cytotoxicity induced by chemotherapy
A. Dose-response…
Figure 6. Impaired PARP1 DNA repair defines…
Figure 6. Impaired PARP1 DNA repair defines chemo-sensitivity
Chemotherapy induces damages in chromosomal DNA in…
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- Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet. 2015;47:458–68. - PubMed
- Brain Neoplasms / drug therapy*
- Brain Neoplasms / genetics
- Cell Line, Tumor
- DNA Repair*
- Dacarbazine / analogs & derivatives
- Dacarbazine / therapeutic use
- Glioma / drug therapy*
- Glioma / genetics
- Humans
- Isocitrate Dehydrogenase / genetics*
- Mutation*
- Phthalazines / therapeutic use
- Piperazines / therapeutic use
- Poly (ADP-Ribose) Polymerase-1 / physiology*
- Temozolomide
- Phthalazines
- Piperazines
- Dacarbazine
- Isocitrate Dehydrogenase
- IDH1 protein, human
- PARP1 protein, human
- Poly (ADP-Ribose) Polymerase-1
- olaparib
- Temozolomide
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 4. Dysfunction of the PARP1 DNA…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5380481/bin/nihms-849346-f0004.jpg)
Figure 5. Targeting the PARP DNA repair…
Figure 5. Targeting the PARP DNA repair pathway enhanced cytotoxicity induced by chemotherapy
A. Dose-response…
Figure 6. Impaired PARP1 DNA repair defines…
Figure 6. Impaired PARP1 DNA repair defines chemo-sensitivity
Chemotherapy induces damages in chromosomal DNA in…
![Figure 5. Targeting the PARP DNA repair…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5380481/bin/nihms-849346-f0005.jpg)
![Figure 6. Impaired PARP1 DNA repair defines…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5380481/bin/nihms-849346-f0006.jpg)
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Source: PubMed