Researchers Show How Resistance of Gliomas to Chemotherapy Drug Temozolomide Occurs

Researchers Show How Resistance of Gliomas to Chemotherapy Drug Temozolomide Occurs

An international team of researchers has discovered why certain gliomas develop resistance to the chemotherapy drug temozolomide.

Gliomas are the most common type of brain tumor and can occur in any location in the brain or spinal cord where glial cells are located. Glial cells are non-neuronal cells in the nervous system that are not involved in the generation of electrical impulses, instead they provide support and protection for neurons, help maintain homeostasis, and produce myelin. Gliomas start in the glial cells and can be life threatening, depending on their size, rate of growth, and where they form.

Treatment involves surgery, or a combination of radiation therapy and chemotherapy, with the latter involving the drug temozolomide (TMZ). One of the problems with temozolomide is between 40% and 50% of individuals are resistant to the drug.

Researchers from the Spanish National Cancer Research Center (CNIO) and the Hong Kong University of Science and Technology (HKUST) determined that a subset of patients acquires a genetic alteration which evades combination radiation therapy and chemotherapy.

The researchers note that temozolomide is a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The drug causes DNA damage in gliomas, with the damage causing the cells to collapse. However, gliomas can repair the damage to the DNA caused by the drug with an enzyme encoded by the MGMT gene. In patients where MGMT activity is blocked, the damaged DNA cannot be repaired and the cancer cells collapse.

In some patients, there is translocation of the MGMT gene, which sees the gene fuse with other genes and is then regulated by the promoters of those genes, resulting in overexpression. Because of the overexpression, the DNA damaged caused by TMZ is repaired very quickly and efficiently, which means that even though TMZ continues to be provides during treatment, the gliomas continue to grow.

“MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation,” wrote the researchers in the paper. “By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo.”

The researchers found that the translocation of the gene is not present in the original tumor, only in recurrent tumors that appear after the original tumor has been treated. That suggests the translocation occurs as a result of the treatment with TMZ.

“When methylated, the MGMT gene is silenced and the patient is predicted to respond to temozolomide. The study showed this method is no longer valid when there has been a genetic translocation. The promoter might still be blocked, but the gene is being overactivated by other promoters and hence could contribute to tumor recurrence,” Said Massimo Squatrito, PhD, head of the Seve Ballesteros Foundation Brain Tumor Group at the CNIO, and lead researcher of the study.

The researchers hope that if their findings are validated in patients, it could prove useful in identifying resistance to TMZ early.

You can read more about the study in the paper – MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas – which was recently published in Nature Communications. DOI: 10.1038/s41467-020-17717-0

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