Gliomas, including glioblastoma (GBM, grade IV) and lower grades (grade II and III) gliomas are the most common and aggressive brain tumors. At present, temozolomide (TMZ) is an oral chemotherapy drug recommended to all GBMs and high-risk lower-grade gliomas. Unfortunately, up to 40-50% of patients are intrinsically resistant to TMZ. Prof. Jiguang Wang and his collaborators from the Beijing Tiantan Hospital and the Spanish National Cancer Research Center elucidated the mechanism of resistance to TMZ in a subset of glioma patients and published their research in Nature Communications. Their work provides the foundation for personalized chemotherapy and potentially leads to methods for overcoming drug resistance in cancer patients.
TMZ can methylate DNA at the O-6 positions of guanine, which is one of the four chemical bases in DNA. The production of methylated guanine at the O-6 position (O6-Methylguanine) can cause DNA double-strand breaks and cell cycle arrest resulting in cell death. However, some cells can repair this type of DNA damage by expressing MGMT (O-6-methylguanine-DNA methyltransferase), therefore reducing the therapeutic effect of TMZ.
Epigenetic silencing of the MGMT gene, by methylating its promoter, can prevent the production of MGMT protein; hence increasing the cell sensitivity to the effect of TMZ. The research team discovered that around 3% of recurrent glioma patients have genomic rearrangements that cause MGMT overexpression regardless of its promoter methylation status. The team used the CRISPR-Cas9 genomic editing tool to replicate some of these genomic rearrangements in different cell and animal models and confirmed that these alterations in the genome, especially the translocation in chromosome 10, drive chemotherapy resistance.
Prof. Wang commented, “For cancer biology, this study advances the understanding of the drug resistance mechanism, and it might shed light on new ideas to overcome this problem. For glioma patients, the finding from this study will provide a biomarker to identify patients who will not benefit from TMZ chemotherapy.”
This research work was accomplished through an international collaboration between Beijing Tiantan Hospital (providing clinical patients), Spanish National Cancer Research Center (performing biological experiments for validation) and HKUST (Wang lab, carrying out computational analysis by identifying and characterizing the key genetic event, i.e. the hypermutation and novel MGMT translocation). In particular, Quanhua Mu is the co-first author (Bioengineering student), Zhaoshi Bao is a contributing author (Postdoctoral fellow at LIFS) and Prof. Wang is the corresponding author.
Oldrini B, Vaquero-Siguero N, Mu Q, Kroon P, Zhang Y, Galan-Ganga M, Bao Z, Wang Z, Liu H, Sa JK, Zhao J, Kim H, Rodriguez-Perales S, Nam D, Verhaak RGW, Rabadan R, Jiang T, Wang J, Squatrito M. MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas. Nat Commun. 2020 Aug 11;3883. doi: 10.1038/s41467-020-17717-0.
