UNIST·IBS Researchers Find Clue to Overcome Drug Resistance in Glioblastoma

Whole Genome Analysis of 427 Cell Lines to Identify Target Genes

Specific Enzyme Activity Involved in Aging and Anticancer Drug Resistance Revealed

Researchers from UNIST and the Institute for Basic Science (IBS) have found a clue that could neutralize the chemotherapy resistance of glioblastoma.

Glioblastoma is a malignant brain tumor with a five-year mortality rate of nine out of ten patients. Currently, temozolomide (TMZ) is the only chemotherapy drug that can directly attack glioblastoma.

The research team led by Professor Anton Gartner of the Graduate School of Medical Science at UNIST (President Jongrae Park), in collaboration with Professor Semin Lee’s team from the Department of Biomedical Engineering and the IBS Genome Stability Research Center, reported that APE1 and other genes are promising target genes to overcome chemotherapy resistance in glioblastoma. It is expected that combining drugs that inhibit the proteins encoded by these target genes with TMZ could enhance therapeutic effects.

UNIST and IBS joint research team. Front row from the left: Anton Gartner, Distinguished Professor at UNIST; Taeju Hwang, Researcher at UNIST; Dmitry Ivanov, Research Fellow at IBS. Photo by UNIST

TMZ and other cytotoxic chemotherapy drugs work by inducing damage to cellular DNA, but cancer cells respond by repairing the DNA damage themselves, making chemotherapy treatment difficult.

To investigate the correlation between DNA repair pathways and cellular TMZ resistance, the research team created cell lines in which one or more of 47 protein-coding genes involved in 19 DNA damage repair pathways were inactivated, and then analyzed their sensitivity to TMZ.

Experimental results showed that suppressing the expression of the APE1 protein improved chemotherapy sensitivity even in TMZ-resistant cells deficient in MMR genes. MMR gene deficiency is one of the causes of TMZ resistance.

On the other hand, suppressing the expression of the MPG protein did not affect chemotherapy sensitivity. Although both APE1 and MPG proteins participate in the BER repair pathway, they showed opposite effects.

The research team analyzed that the reason why suppressing MPG protein expression did not improve chemotherapy resistance is that cells use an alternative repair pathway called TLS. They explained that protein-coding genes involved in the TLS pathway could also be targets for suppressing chemotherapy resistance, and they plan to conduct further research in this area.

This study also newly revealed the relationship between chemotherapy resistance and aging. The DNA mutation patterns known to accumulate with aging were similar to the DNA mutation patterns accumulated in cells responding to TMZ. This suggests that TLS polymerase zeta, one of the TLS polymerases, is the cause of mutation accumulation in both aging and TMZ-resistant cells.

Professor Lee Semin, UNIST.

The joint research team stated, “This is significant in that it provides important clues for precision medicine research such as chemotherapy targeting vulnerabilities in DNA repair processes and aging prevention.”

This study was co-corresponded by Research Fellow Dmitry Ivanov of the IBS Genome Stability Research Center, with Taeju Hwang, a researcher from the Department of Biomedical Engineering at UNIST, as the first author.

The research results were published in the international journal Nucleic Acids Research on December 5, and the research was supported by the National Research Foundation of Korea and the Institute for Basic Science.

This content was produced with the assistance of AI translation services.