Targeting the molecular mechanisms of glioma stem cell resistance to chemotherapy

Abstract Glioma stem cells (GSCs) are a subpopulation of glioblastoma cells that display high levels of cellular plasticity. They possess functional characteristics that permit sustained self-renewal, persistent proliferation, and tumor initiation. In addition, they have an intrinsic ability to invade through the brain parenchyma, evade the immune system, adapt to microenvironmental pressures, and promote angiogenesis. Adaptive interactions between GSCs and their biological niches in the brain microenvironment offer them a safe haven from drugs that cannot cross the blood-brain barrier. Furthermore, GSC inherent resistance to treatment renders standard of care therapy futile, leading to tumor progression and recurrence. As such, GSCs have been blamed for clinical deterioration and dismal survival outcomes in patients with glioma. Mechanisms of GSC resistance include O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, enhanced repair of DNA damage, impaired induction of apoptosis, aberrant DNA checkpoint analysis, expression of ATP-binding cassette (ABC) transporters and multidrug resistance, and phenotypic plasticity. Understanding the molecular mechanisms of GSC chemoresistance allows the development of efficient therapeutic strategies to overcome it. Pro-differentiation therapies, including bone morphogenic proteins (BMPs) and posttranscriptional modification using microRNAs (miRNAs), drive GSCs into more differentiated states, sensitizing them to cytotoxic treatments. Targeting of the immunogenic, neuronal, hypoxic, and/or angiogenic niches of GSCs offer promising therapeutic potential. Intracellularly, inhibition of the cell signaling pathways that promote GSC survival and progression is essential for reversing GSC chemotherapeutic resistance. So far, the translation of monotherapeutic agents to the clinical scene failed to instigate the desired clinical benefit in patient outcomes. Therefore, the combination of therapeutic strategies holds promise as efforts to overcome GSC resistance continue to build. Technological advances in single-cell genomics and CRISPR-Cas9 genome-editing tools and derivatives offer better opportunities to achieve strides in precision cancer therapeutics.