Therapy enhancing chromosome instability may be advantageous for <i>IDH1</i>R132H/WT gliomas

Recently revised brain tumor classification suggested a glioma treatment strategy that takes into consideration molecular variants in <i>IDH1</i> and <i>TP53</i> marker genes. While pathogenic variants of IDH1 and TP53 can be accompanied by chromosomal instability (CIN), the impact of <i>IDH1</i> and <i>TP53</i> 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 <i>IDH1</i> and <i>TP53</i> on chromosome transmission and demonstrated that IDH1R132H and TP53R248Q variants elevate CIN. We next found enhanced CIN levels and the sensitivity of <i>IDH1</i> ^R132H/WT and <i>TP53</i> ^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 <i>IDH1</i> ^R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring <i>IDH1</i> ^R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the <i>IDH1</i> ^R132H/WT genotype could be advantageous for adjuvant treatment.