Molecular Mechanisms of Treatment Resistance in Glioblastoma

Abstract

Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms underlying treatment failure, the standard-of-care therapy has not changed over the last two decades, signifying a great unmet need. The challenges of treating glioblastoma are many and include inadequate drug or agent delivery across the blood-brain barrier, abundant intra- and intertumoral heterogeneity, redundant signaling pathways, and an immunosuppressive microenvironment. Here, we review the innate and adaptive molecular mechanisms underlying glioblastoma's treatment resistance, emphasizing the intrinsic challenges therapeutic interventions must overcome-namely, the blood-brain barrier, tumoral heterogeneity, and microenvironment-and the mechanisms of resistance to conventional treatments, targeted therapy, and immunotherapy.

Keywords: chemoresistance; glioblastoma; heterogeneity; immunotherapy; radioresistance; targeted therapy.

Figure 1

Anatomic, cellular and molecular basis of treatment resistance in GBM. The tumoral microenvironment of GBM consists of the blood–brain barrier and a number of important populations of cells: glioma cells, glioma stem cells, and various important immune cells including tumor-associated macrophages, tumor-infiltrating lymphocytes, and myeloid-derived suppressor cells. Crosstalk between these cells occurs via involves various cytokines and growth factors, the net effect of which results in a stemness-promoting, proliferative, angiogenic, and immunosuppressive milieu.

Figure 2

The molecular basis of chemoresistance in GBM. The major mechanisms of resistance of GBM to alkylating chemotherapy such as temozolomide (TMZ) revolve around DNA repair, cell cycle progression, and anti-apoptosis. One major resistance pathway involves the enzyme O6-MeG DNA methyltransferase (MGMT), which removes TMZ-induced O6 methyl adducts to allow DNA replication to continue. Acquired DNA mismatch repair deficiency also contributes to alkylating agent resistance. As cells acquire TMZ resistance, downregulation of DNA methyltransferase-1 occurs, leading to epigenetic de-repression of oncogenes such as SNHG12 that activate MAPK signaling to lead to inhibition of apoptosis and G1/S transition.

Figure 3

The molecular basis of radioresistance in GBM. Resistance to radiotherapy in GBM occurs via microenvironmental crosstalk across multiple signaling pathways (e.g., Wnt, Notch, c-Met, STAT3, Sonic hedgehog, and NF-κB) that collectively maintain intrinsically-radioresistant glioma stem cell populations. Within these GSCs, aberrantly upregulated DNA damage response occurs via activation of repair enzymes such as the DNA-dependent protein kinase (DNA-PK) which promotes non-homologous end joining.