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Alterations in Molecular Profiles Affecting Glioblastoma Resistance to Radiochemotherapy: Where Does the Good Go?
Juliana B Vilar1, Markus Christmann1, Maja T Tomicic1
1Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
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.
Insights
Glioblastoma multiforme (GBM) cells resist standard treatments by activating DNA repair, autophagy, and stemness pathways. Cellular senescence and inflammation further contribute to treatment resistance in this aggressive brain tumor.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Medicine
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor survival rates, often recurring after treatment.
- Current treatments include surgery, radiation, and temozolomide (TMZ), but GBM's heterogeneity and mutations lead to resistance.
- GBM cells evade apoptosis and utilize mechanisms like DNA repair, autophagy, stemness, and senescence to survive treatment.
Purpose of the Study:
- To highlight the mutational background of GBM and its impact on treatment response.
- To discuss molecular mechanisms underlying GBM resistance to radiochemotherapy.
- To explore future perspectives for overcoming treatment resistance in GBM.
Main Methods:
- Review of recent evidence on molecular mechanisms of GBM resistance.
- Analysis of GBM cell responses to standard treatments like ionizing radiation and TMZ.
- Investigation of pathways involved in treatment-induced adaptation and survival.
Main Results:
- GBM cells exhibit high heterogeneity and intrinsic mutations affecting major cellular pathways.
- Standard treatments like TMZ and radiation induce DNA repair, autophagy, stemness, and senescence in GBM cells.
- Cellular senescence upon TMZ exposure, along with enhanced DNA repair and autophagy, promotes GBM resistance and tumor recurrence.
Conclusions:
- GBM's intrinsic mutations and adaptive responses significantly interfere with the efficacy of standard radiochemotherapy.
- Understanding the molecular mechanisms of resistance, including senescence and inflammation, is crucial for developing new therapeutic strategies.
- Targeting these resistance pathways offers future perspectives for combating incurable GBM.
