Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1

Cancer Science
Hiroaki FujiwaraKazuhiko Koike

Abstract

Cholangiocarcinoma is a life-threatening disease with a poor prognosis. Although genome analysis unraveled some genetic mutation profiles in cholangiocarcinoma, it remains unknown whether such genetic abnormalities relate to the effects of anticancer drugs. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are exclusively found in almost 20% of intrahepatic cholangiocarcinoma (ICC). Recently, the anticancer effects of BET inhibitors including JQ1 have been shown in various tumors. In the present study, we report that the antigrowth effect of JQ1 differs among ICC cells and IDH1 mutation sensitizes ICC cells to JQ1. RBE cells harboring IDH1 mutation was more sensitive to JQ1 than HuCCT1 or HuH28 cells with wild-type IDH1. JQ1 induced apoptosis only in RBE cells through the upregulation of proapoptotic genes BAX and BIM. We found that the antigrowth effect was not attributed to downregulation of the MYC gene as a well-known target of JQ1 in various cancer cells. Notably, the forced expression of mutant IDH1 successfully sensitized HuCCT1 cells to JQ1. In addition, AGI-5198, a selective inhibitor of mutant IDH1 partially reversed the decrease in viability after JQ1 treatment and also suppressed the JQ1-induced apoptosis in RB...Continue Reading

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Jun 6, 2019·Frontiers in Oncology·Danielle GolubDimitris G Placantonakis
Aug 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fabiana CrispoMatteo Landriscina
Apr 15, 2021·Molecular Therapy Oncolytics·Hua YangHua You
Jun 1, 2021·Signal Transduction and Targeted Therapy·Lei ZhongShengyong Yang

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Methods Mentioned

BETA
PCR
immunoprecipitation
flow cytometry

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