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Combined bioinformatic and clinical assay uncovers resistance and susceptibility mechanisms of human glioblastomas to temozolomide and identifies new survival biomarkers outperforming MGMT promoter methylation

ABSTRACT: Glioblastoma (GBM) is the most aggressive and lethal CNS tumor with only 14 months median overall survival after diagnosis and ∼5% 5-years survival rate. The treatment strategy is mainly surgery and/or radiation therapy, both combined with adjuvant temozolomide (TMZ) chemotherapy. TMZ treatment results in methylation of DNA purine bases, where the primary cytotoxic lesion is O6-methylguanine that can be removed by DNA repair enzyme methylguanine methyltransferase (MGMT) when tumors express this protein. Historically, methylation of MGMT gene promoter is used as the major biomarker predicting individual tumor response to TMZ, but there are also additional biomarkers. However, most of them were developed using TCGA project collection of molecular profiles which were unproperly diagnosed as GBM and now need to be reclassified according to the most recent WHO CNS5 tumor classification. Here we for the first time compared biomarker potentials of MGMT methylation, expression levels of 361 DNA repair genes, and activation levels of 38 DNA repair pathways on updated TCGA and other samplings and validated the results on our experimental multicenter GBM patient cohort (n=50). We found that expression/activation levels of 7 and 6 emerging gene/pathway biomarkers served as high-quality positive (HR<0.61) and negative (HR>1.63), respectively, patient survival biomarkers, all performed significantly better than MGMT methylation. Positive survival biomarkers were enriched in the processes of ATM-dependent checkpoint activation and cell cycle arrest whereas negative – in excision DNA repair. We also built and characterized gene signature which was informative for GBM patient survival following TMZ administration (HR 0.27-0.44, p<0,0004; AUC 0.69-0.9).

ORGANISM(S): Homo sapiens

PROVIDER: GSE263890 | GEO | 2024/04/17

REPOSITORIES: GEO

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Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

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Combined bioinformatic and clinical assay uncovers resistance and susceptibility mechanisms of human glioblastomas to temozolomide and identifies new survival biomarkers outperforming MGMT promoter methylation

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