Temozolomide Induced Hypermutation in Glioma: Evolutionary Mechanisms and Therapeutic Opportunities

Abstract

Glioma are the most common type of malignant brain tumor, with glioblastoma (GBM) representing the most common and most lethal type of glioma. Surgical resection followed by radiotherapy and chemotherapy using the alkylating agent Temozolomide (TMZ) remain the mainstay of treatment for glioma. While this multimodal regimen is sufficient to temporarily eliminate the bulk of the tumor mass, recurrence is inevitable and often poses major challenges for clinical management due to treatment resistance and failure to respond to targeted therapies. Improved tumor profiling capacity has enabled characterization of the genomic landscape of gliomas with the overarching goal to identify clinically relevant subtypes and inform treatment decisions. Increased tumor mutational load has been shown to correlate with higher levels of neoantigens and is indicative of the potential to induce a durable response to immunotherapy. Following treatment with TMZ, a subset of glioma has been identified to recur with increased tumor mutational load. These hypermutant recurrent glioma represent a subtype of recurrence with unique molecular vulnerabilities. In this review, we will elaborate on the current knowledge regarding the evolution of hypermutation in gliomas and the potential therapeutic opportunities that arise with TMZ-induced hypermutation in gliomas.

Keywords: MGMT; glioma; hypermutation; recurrence; temozolomide.

Figure 1

Evolutionary pathways toward hypermutation. (A) 06-Me-Guanine are generated through TMZ exposure. In the presence of MGMT, methyl adducts are removed and the cell survives without gain in mutagenesis. In the absence of MGMT, MMR status determines survival. In MMR proficient cells, futile repair leads to double strand breaks and cell death. In cells which lose MMR proficiency, cells gain tolerance to base mismatch and cells acquire genomic hypermutation. Suggested therapies are listed below. (B) Stem cell hierarchy of tumor growth may provide an alternate means of resistance to hypermutation. Minor populations of stem cells maintain tumor growth through differentiation. Upon exposure to TMZ, stem cells may be minimally affected by chemotherapy due to greater drug efflux activity and slower proliferation rate and so repopulate tumor mass with non-hypermutant progeny. Alternatively, stem cells which acquire hypermutation will give rise to hypermutant recurrent tumors.