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

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 ( IDH 1/2 ) are exclusively found in almost 20% of intrahepatic cholangiocarcinoma ( ICC ). Recently, the anticancer effects of BET inhibitors including JQ 1 have been shown in various tumors. In the present study, we report that the antigrowth effect of JQ 1 differs among ICC cells and IDH 1 mutation sensitizes ICC cells to JQ 1. RBE cells harboring IDH 1 mutation was more sensitive to JQ 1 than Hu CCT 1 or HuH28 cells with wild‐type IDH 1 . JQ 1 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 JQ 1 in various cancer cells. Notably, the forced expression of mutant IDH 1 successfully sensitized Hu CCT 1 cells to JQ 1. In addition, AGI ‐5198, a selective inhibitor of mutant IDH 1 partially reversed the decrease in viability after JQ 1 treatment and also suppressed the JQ 1‐induced apoptosis in RBE cells. These data suggest that IDH 1 mutation contributed to the growth inhibitory effect of JQ 1 in RBE cells. Furthermore, given that the effect of mutant IDH 1 was not recapitulated in glioblastoma cells, the enhancement of JQ 1 sensitivity by IDH 1 mutation seems to be specific for ICC cells. Our findings propose a new stratified therapeutic strategy based on IDH 1 mutation in ICC .