Alterations in Molecular Profiles Affecting Glioblastoma Resistance to Radiochemotherapy: Where Does the Good Go?

Abstract

Glioblastoma multiforme (GBM) is a brain tumor characterized by high heterogeneity, diffuse infiltration, aggressiveness, and formation of recurrences. Patients with this kind of tumor suffer from cognitive, emotional, and behavioral problems, beyond exhibiting dismal survival rates. Current treatment comprises surgery, radiotherapy, and chemotherapy with the methylating agent, temozolomide (TMZ). GBMs harbor intrinsic mutations involving major pathways that elicit the cells to evade cell death, adapt to the genotoxic stress, and regrow. Ionizing radiation and TMZ induce, for the most part, DNA damage repair, autophagy, stemness, and senescence, whereas only a small fraction of GBM cells undergoes treatment-induced apoptosis. Particularly upon TMZ exposure, most of the GBM cells undergo cellular senescence. Increased DNA repair attenuates the agent-induced cytotoxicity; autophagy functions as a pro-survival mechanism, protecting the cells from damage and facilitating the cells to have energy to grow. Stemness grants the cells capacity to repopulate the tumor, and senescence triggers an inflammatory microenvironment favorable to transformation. Here, we highlight this mutational background and its interference with the response to the standard radiochemotherapy. We discuss the most relevant and recent evidence obtained from the studies revealing the molecular mechanisms that lead these cells to be resistant and indicate some future perspectives on combating this incurable tumor.

Keywords: acquired resistance; apoptosis; autophagy; cellular homeostasis alterations; malignant glioma; mutational background; radiotherapy; senescence; stemness; temozolomide.

Figure 1

Metabolization pathway of temozolomide (TMZ) (A) and the consequences of the main mutagenic lesion (O⁶mG) and N—alkylations on DNA, depending on the DNA repair mechanisms induced (B). For a full description, see the main text.

Figure 2

Flowchart of the most frequent mutations in the relevant pathways involved in primary GBM resistance. Within the boxes outlined in blue are significantly mutated genes (SMG) and in the yellow boxes are the driver-mutated genes. Dashed red boxes group mutated genes of the same pathway and display the relative mutation frequency of the pathway. Adapted from TCGA.

Figure 3

Schematic representation of the RTK pathway (A) and the Wnt canonical (β-catenin dependent) and non-canonical pathways (B). For a detailed description, see the main text.

Figure 4

Major apoptotic pathways: extrinsic (death receptor-mediated), intrinsic (mitochondria-mediated) and perforin/granzyme B pathways. For a full description, consult the main text. The green color signals anti-apoptotic, and the red color apoptotic processes.

Figure 5

Schematic representation of the pathways leading to cell cycle arrest, senescence, and senescence-associated secretory phenotype (SASP) upon exposure to IR and/or TMZ. For a detailed description, refer to the main text.

Figure 6

Autophagy regulation and outcomes upon IR/TMZ exposure leading to radiation and chemoresistance. For a detailed description, see the main text.