Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.

in Acta neuropathologica communications by Hengzeng Li, Yahui Wu, Yue Chen, Jinquan Lv, Chengkang Qu, Tingjie Mei, Yunfan Zheng, Cheng Ye, Feifei Li, Shuo Ge, Anhui Yao, Liyun Jia

TLDR

  • Temozolomide is a chemotherapy used to treat glioma, but resistance mechanisms limit its effectiveness.
  • Researchers have identified multiple pathways contributing to TMZ resistance and are exploring new therapeutic approaches to overcome this resistance.

Abstract

Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients.

Overview

  • The study reviews the molecular pathways contributing to temozolomide (TMZ) resistance in glioma, highlighting the complexity of resistance mechanisms.
  • The review discusses the various resistance factors, including DNA repair mechanisms, genetic mutations, non-coding RNAs, glioma stem cells, autophagy, and tumor microenvironment, among others.
  • The study aims to summarize current developments and emerging areas in overcoming TMZ resistance, with the goal of enhancing clinical outcomes and prolonging survival for glioma patients.

Comparative Analysis & Findings

  • The review highlights the multiple molecular pathways that contribute to TMZ resistance, including enhanced DNA repair mechanisms, genetic mutations, and dysregulated non-coding RNAs, among others.
  • The study discusses the importance of understanding these resistance mechanisms to develop effective therapeutic strategies to overcome TMZ resistance.
  • The review emphasizes the need for combined approaches, including immunotherapeutic interventions, metabolic strategies, and inhibition of efflux transporters, to enhance TMZ effectiveness.

Implications and Future Directions

  • The study identifies emerging areas, such as CRISPR-based gene editing and phytochemical combinations, as potential new therapeutic strategies to overcome TMZ resistance.
  • The review highlights the need for further research to develop and validate novel therapeutic approaches, including repurposed drugs and novel TMZ analogs designed to bypass MGMT-mediated resistance.
  • The study aims to enhance clinical outcomes and prolong survival for glioma patients by understanding and overcoming TMZ resistance, which is a significant challenge in current glioma treatment.
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