Mechanisms of Chemoresistance in High-Grade Gliomas Publisher



Asl M S ; Iranmehr A ; Hanaei S
Source: Interdisciplinary Cancer Research Published:2025

Abstract

Background Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype GBM, is classified by the World Health Organization (WHO) as a grade 4 tumor and is recognized as high-grade gliomas (HGGs). While contemporary therapeutic modalities have made strides in the management of various malignancies, glioblastoma (GBM) persists as a primary brain tumor that retains its aggressive behavior and poor prognosis. Current treatments, such as surgical resection, radiation, and chemotherapy, have been largely unable to alter these inherent characteristics of GBM. One key obstacle has been the tumor’s intrinsic and acquired resistance to chemotherapy, which substantially limits the effectiveness of pharmacological interventions. Methods A comprehensive review of the literature was conducted to elucidate the etiological factors and primary mechanisms that underpin the chemoresistance observed in GBM. A literature search was conducted on PubMed based on the keywords “Glioblastoma,” “Chemoresistance,” “Temozolomide,” and “Temozolomide resistance” to identify relevant studies and articles related to mechanisms of chemoresistance in GBM. This review focused on the mechanisms involved in DNA damage repair, key signaling pathways, role of noncoding RNAs, and some other mechanisms that have been studied to date. Results Our review unraveled the complex mechanisms behind GBM’s formidable chemoresistance. Primarily, the role of glial stem cells was identified as a significant hurdle. Additionally, we explored the genetic heterogeneity in GBM, emphasizing how diverse mutations and alterations in multiple signaling pathways contribute to the tumor’s adaptive resistance. These combined insights not only offer a deeper understanding of the chemoresistant nature of GBM but also suggest promising avenues for therapeutic innovation, potentially revolutionizing the treatment paradigm for this aggressive malignancy. Conclusion GBM presents a profound therapeutic challenge due to its inherent and adaptive chemoresistance. This resistance is influenced by a myriad of factors, from the protective role of glial stem cells to the tumor’s genetic heterogeneity and complex signaling pathways. The Warburg effect and drug efflux mechanisms further complicate treatment approaches. A comprehensive understanding of these mechanisms is imperative for the development of effective therapeutic interventions against this aggressive tumor. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023.