CBIO-20. HIGH LEVELS OF TERT CONFER SENSITIVITY TO THE DNA HYPOMETHYLATING AGENT DECITABINE (DAC) IN GLIOMAS

BACKGROUND Decitabine (DAC)-incorporated DNA binds DNMT1 enzyme and subsequently triggers DNMT1 degradation. Previously, we showed that DAC can mediate the anti-tumor effect in a preclinical model of IDH-mutant gliomas. Here, we further investigate molecular determinants of response to DAC in gliomas. METHODS DAC response was assessed by soft agar anchorage independent growth assays and cell proliferation measurements. Patient-derived IDH-mutant chromosome 1p/19q codeleted (codel) and non-codel glioma lines upon vehicle and DAC treatment were used for RNA sequencing and Gene Set Enrichment Analysis (GSEA). RESULTS We found that DAC treatment is effective in high TERT-expressing gliomas including IDH-mutant and IDH-wildtype glioma lines. In contrast, pharmacological inhibition of TERT reduces DAC response in glioma lines. Interestingly, transcriptomic profiling showed that DAC reduces the expression of TERT, along with increased CDKN1A/p21 expression. We experimentally validated that TERT expression depends on CDKN1A/p21. Furthermore, p53 is required for DAC-mediated CDKN1A/p21 induction. Importantly, DAC-mediated proliferation defects in TERT-proficient glioma cells are abolished by DNMT1 knockdown, indicative of an expected DAC mechanism. CONCLUSIONS DAC could elicit the pronounced anti-tumor response in IDH-mutant codel oligodendroglioma and IDH-wildtype glioblastoma with TERT activating mutations.