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

Simple Summary Glioblastoma is a type of brain cancer that remains incurable. Despite multiple past and ongoing preclinical studies and clinical trials, involving adjuvants to the conventional therapy and based on molecular targeting, no relevant benefit for patients' survival has been achieved so far. The current first-line treatment regimen is based on ionizing radiation and the monoalkylating compound, temozolomide, and has been administered for more than 15 years. Glioblastoma is extremely resistant to most agents due to a mutational background that elicits quick response to insults and adapts to microenvironmental and metabolic changes. Here, we present the most recent evidence concerning the molecular features and their alterations governing pathways involved in GBM response to the standard radio-chemotherapy and discuss how they collaborate with acquired GBM's resistance. 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.