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REVIEW
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 68-82

A multifaceted review of temozolomide resistance mechanisms in glioblastoma beyond O-6-methylguanine-DNA methyltransferase


1 Department of Surgery, Division of Neurosurgery, Prince of Wales Hospital, Sha Tin, Hong Kong Special Administrative Region, China
2 Department of Clinical Oncology, Prince of Wales Hospital, Sha Tin, Hong Kong Special Administrative Region, China

Correspondence Address:
Prof. Wai-Sang Poon
Department of Surgery, Division of Neurosurgery, Prince of Wales Hospital, 4/F Lui Che Woo Clinical Sciences Building, Sha Tin, Hong Kong Special Administrative Region
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_3_19

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Temozolomide (TMZ), an oral alkylating agent, is a cornerstone of standard-of-care multimodality therapy for glioblastoma. In spite of significant efforts to treat this disease, the tumor carries a poor prognosis and is considered incurable largely due to the development of chemoresistance. One of the main mechanisms for this phenomenon is the activation of tumor DNA repair systems, such as O-6-methylguanine-DNA methyltransferase, that removes TMZ-induced DNA adducts and restores genomic integrity. Recent advances in the understanding of TMZ resistance oncobiology have introduced several novel independent molecular mechanisms involving epigenetic, transcriptomic, proteomic aberrations as well as alterations in apoptosis-autophagy processes, receptor tyrosine kinase activity, the tumor microenvironment, and the emergence of glioma stem cells. This article describes a multifaceted summary of the latest proposed causes for TMZ resistance and their complex interactions. It is believed that only by comprehending this growing network of interdependent mechanisms can effective combinatorial oncologic therapeutic strategies be developed to improve patient overall survival.


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