TERT and DNMT1 expression predict sensitivity to decitabine in gliomas

Area of Science:

• Neuro-oncology
• Cancer epigenetics
• Pharmacology

Background:

• Decitabine (DAC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor used for myelodysplastic syndromes.
• Preclinical studies indicate DAC possesses antitumor activity against gliomas with isocitrate dehydrogenase 1 (IDH1) mutations.
• A clinical trial is investigating DAC efficacy in IDH-mutant gliomas, necessitating assessment of response determinants.

Purpose of the Study:

• To comprehensively assess the efficacy of Decitabine (DAC) in malignant gliomas.
• To identify potential determinants of response to DAC treatment in IDH-mutant gliomas.

Main Methods:

• Patient-derived IDH1-mutant and -wildtype glioma lines were used to assess the effects of DAC and telomerase inhibitors.
• RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and correlation analyses were performed.
• Manipulation of telomerase reverse transcriptase (TERT) and DNMT1 expression and activity was conducted.

Main Results:

• IDH1-mutant gliomas with 1p/19q codeletion were sensitive to DAC, with inhibited DNA replication genes.
• DAC treatment induced cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A) expression and downregulated TERT.
• TERT overexpression increased DNMT1 levels and DAC sensitivity; DNMT1 inhibition abrogated DAC response in TERT-proficient cells.

Conclusions:

• Decitabine (DAC) downregulates TERT through p21 induction in IDH-mutant gliomas.
• TERT and DNMT1 expression levels are identified as potential determinants of response to DAC.
• Findings support further investigation of DAC in IDH-mutant gliomas, with TERT and DNMT1 as predictive biomarkers.