Therapy enhancing chromosome instability may be advantageous for IDH1 R132H/WT gliomas.

Abstract

Recently revised brain tumor classification suggested a glioma treatment strategy that takes into consideration molecular variants in IDH1 and TP53 marker genes. While pathogenic variants of IDH1 and TP53 can be accompanied by chromosomal instability (CIN), the impact of IDH1 and TP53 mutations on genome stability remains unstudied. Elevated CIN might provide therapeutic targets, based on synergistic effects of chemotherapy with CIN-inducing drugs. Using an assay based on human artificial chromosomes, we investigated the impact of common glioma missense mutations in IDH1 and TP53 on chromosome transmission and demonstrated that IDH1R132H and TP53R248Q variants elevate CIN. We next found enhanced CIN levels and the sensitivity of IDH1 ^R132H/WT and TP53 ^R248Q/R248Q genotypes, introduced into U87 MG glioma cells by CRISPR/Cas9, to different drugs, including conventional temozolomide. It was found that U87 MG cells carrying IDH1 ^R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring IDH1 ^R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the IDH1 ^R132H/WT genotype could be advantageous for adjuvant treatment.