The Role of Cancer Stem Cells in Drug Resistance and Relapse

Glioblastoma multiforme (GBM) demonstrated the most lethal form of the primary brain tumors. It is characterized by rapid cell proliferation and invasiveness, along with tremendous resistance to standard chemotherapies. Contemporary treatment strategies were found to be ineffective due to intratumoral heterogeneity and resistance mechanisms, with the adaptive features of specific molecular signatures, as well as drug resistance, which confound treatment responses and outcomes. Oncologists have shown correlates of GBM drug-resistance with glioblastoma stem cells (GSCs). Notably, current literature is shedding light upon this relationship. In contrast, important biomarkers associated with GSCs must have the potential to identify drug-resistant cancer cell populations. GSCs are a defined cell compartment based on specific molecular characteristics of their cell phenotype, including these specific markers—Nestin, CD133, miR-128, Major Vault Protein, and others: hence, targeting GSCs clears the field regarding drug resistance mechanisms which can ultimately inform therapy against complete resistance (or obstruction of treatment) before or after treatment phases and better outcomes in patients experiencing cancer. Research has shown similar success in transition with clinical trials that were targeting specific GSC markers and possible cellular signaling pathways to cancer therapies. However, they still face relational reversibility and several translational barriers that are critically related to tumor plasticity and immune exclusion mechanisms. Further discovery of novel biomarkers and understanding of the molecular landscape of treatment resistance in GBM, with the advent of cutting-edge technologies like single-cell RNA sequencing, CRISPR-Cas9 gene editing, and nanotechnology, is paving the way to overcome these challenges. In addition, computational modeling and artificial intelligence are now finding applications in the study of complex genomic data, prediction of treatment outcome, and the discovery of new therapeutic targets in glioblastoma. To improve patient outcomes in GBM, we need to initiate the development of personalized approaches based on patient-specific treatment resistance and the greater risk of cancer relapse.