Supplementary Data from Glioblastoma Therapy Can Be Augmented by Targeting IDH1-Mediated NADPH Biosynthesis

Wahl, Daniel R.; Dresser, Joseph; Wilder-Romans, Kari; Parsels, Joshua D.; Zhao, Shuang G.; Davis, Mary; Zhao, Lili; Kachman, Maureen; Wernisch, Stefanie; Burant, Charles F.; Morgan, Meredith A.; Feng, Felix Y.; Speers, Corey; Lyssiotis, Costas A.; Lawrence, Theodore S.

doi:10.1158/0008-5472.22416176.v1

Supplementary Data from Glioblastoma Therapy Can Be Augmented by Targeting IDH1-Mediated NADPH Biosynthesis

journal contribution

posted on 2023-03-31, 01:04 authored by Daniel R. Wahl, Joseph Dresser, Kari Wilder-Romans, Joshua D. Parsels, Shuang G. Zhao, Mary Davis, Lili Zhao, Maureen Kachman, Stefanie Wernisch, Charles F. Burant, Meredith A. Morgan, Felix Y. Feng, Corey Speers, Costas A. Lyssiotis, Theodore S. Lawrence

Supplementary Table 1: Experimental Details of Mass Spectrometry Supplemental Figure 1: Effects of IDH1 KD on radiation-induced apoptosis and autophagy. Effect of low dose radiation on expression of NADPH-producing enzymes Supplemental Figure 2: Effect of IDH1 KD on radiation induced DNA double strand break repair and homologous recombination repair Supplemental Figure 3: Cell cycle effects of IDH1 knockdown. Supplemental Figure 4: Effects of doxycycline and radiation on control i-shNT xenografts.

Funding

NCI

NIH

University of Michigan

History

ARTICLE ABSTRACT

NADPH is a critical reductant needed in cancer cells to fuel the biosynthesis of deoxynucleotides and antioxidants and to sustain stress-survival responses after radiation-induced DNA damage. Thus, one rational strategy to attack cancer cells is to target their heavy reliance on NADPH. Here, we report that the isocitrate dehydrogenase IDH1 is the most strongly upregulated NADPH-producing enzyme in glioblastoma (GBM). IDH1 silencing in GBM cells reduced levels of NADPH, deoxynucleotides, and glutathione and increased their sensitivity to radiation-induced senescence. Rescuing these metabolic restrictions was sufficient to reverse IDH1-mediated radiosensitization. In a murine xenograft model of human GBM, we found that IDH1 silencing significantly improved therapeutic responses to fractionated radiotherapy, when compared with either treatment alone. In summary, our work offers a mechanistic rationale for IDH1 inhibition as a metabolic strategy to improve the response of GBM to radiotherapy. Cancer Res; 77(4); 960–70. ©2016 AACR.