AUTHOR=Abe Hideaki , Natsumeda Manabu , Okada Masayasu , Watanabe Jun , Tsukamoto Yoshihiro , Kanemaru Yu , Yoshimura Junichi , Oishi Makoto , Hashizume Rintaro , Kakita Akiyoshi , Fujii Yukihiko 

TITLE=MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01568

DOI=10.3389/fonc.2019.01568

ISSN=2234-943X

ABSTRACT=<p>Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase (<italic>MGMT</italic>) promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with <italic>HIST1H3B</italic> K27M and <italic>ACVR1</italic> G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with <italic>H3F3A</italic> gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze <italic>MGMT</italic> promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated <italic>MGMT</italic> promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with <italic>H3F3A</italic> gene mutation showed <italic>MGMT</italic> promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment <italic>in vitro</italic>. We confirmed <italic>in vitro</italic> that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.</p>