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.

Anticancer Potential of Temozolomide-Loaded Eudragit-Chitosan Coated Selenium Nanoparticles: In Vitro Evaluation of Cytotoxicity, Apoptosis and Gene Regulation

“…Resistance to TMZ is a major cause of recurrence of GBM, resulting in high mortality of GBM worldwide [ 2 , 8 ]. The molecular mechanisms involved in TMZ resistance in GBM patients have been described [ 39 , 40 ]. Therefore, the effectiveness of anti-cancer drugs could be improved by utilizing approaches to control these molecular factors.…”

Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

“…The tumor microenvironment is surrounded by cytokines, chemokines, and growth factors to recruit immune cells to enable tumor growth and progression, seriously affecting the therapeutic cure (Figure 3). Examples for cells in this niche are B cells and T cells, such as T regulatory cells (Tregs), so-called tumorinfiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and bloodbrain barrier cells, which communicate by secreted mediators to facilitate cell growth, invasion, therapeutic resistance, and immune evasion (Ou et al, 2020).…”

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy

“…Radioresistance of GB GB tumors have been identified as therapy resistant due to multiple molecular mechanisms including inadequate drug blood-brain barrier (BBB) passage, intra-and intertumoral heterogeneity, redundant signaling pathways resulting in rescue mechanisms, adaptive radioresistance and an immunosuppressive tumor micro-environment (TME) promoted by a chronic state of hypoxia (15,(42)(43)(44). Hypoxic niches limiting the formation of reactive oxygen species (ROS) and a hyperactivation of the DNA damage response machinery induced by glioma stem cells (GSC) contribute to glioma radioresistance (44,45).…”

“…Hypoxic niches limiting the formation of reactive oxygen species (ROS) and a hyperactivation of the DNA damage response machinery induced by glioma stem cells (GSC) contribute to glioma radioresistance ( 44 , 45 ). In addition, a cross-talk between TME populations via shared pathways, such as STAT3, Wnt and Notch play a role ( 15 , 46 ).…”

“…Treatment challenges often derive from the molecular and cellular heterogeneity inherent to these tumors. They include innate and acquired resistance with subpopulations of tumor cells harboring stem-like properties rendering them more resistant to therapy (13)(14)(15). Another major challenge in GB patients is tumor recurrence, which is unfortunately inevitable and results in a more aggressive and radioresistant secondary tumor.…”