Year: 2016
Type: conference-abstract
Abstract: Malignant gliomas are the most frequent and lethal cancers of the central nervous system. Despite multimodal therapy with radiation and the alkylating agent temozolomide (TMZ), the disease remains incurable and ultimately fatal. Up to 90% grades II-III gliomas contain a single base substitution in one isocitrate dehydrogenase 1 (IDH1) allele. IDH1 converts isocitrate to a-ketoglutarate (aKG) while the mutant form of the enzyme converts aKG to D-2-hydroxyglutarate (D2HG). The IDH1 mutation is associated with resistance to TMZ; however, the resistance mechanism remains unclear and there is no available means of sensitizing IDH1 mutant cells to TMZ. We now show that increased resistance to TMZ is due to a G2 DNA damage checkpoint override and that this checkpoint adaptation is mediated by an increase in PLK1 activity. Importantly, we generated IDH1 mutant tumors in mice and demonstrated that the anti-tumor efficacy of BI2536 and TMZ in combination is significantly better than either drug alone as the combination treatment was able to achieve complete tumor regression. We conclude that mutant IDH1 promotes TMZ resistance and G2 checkpoint bypass with damaged DNA. Additionally, this checkpoint adaptation is facilitated by activation of PLK1, which can be exploited therapeutically with the combination of TMZ and a PLK1 inhibitor, suggesting PLK1 inhibitors may be clinically valuable in the treatment of IDH1 mutant gliomas.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2575941538