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

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 RBE cells. These data suggest that IDH1 mutation contributed to the growth inhibitory effect of JQ1 in RBE cells. Furthermore, given that the effect of mutant IDH1 was not recapitulated in glioblastoma cells, the enhancement of JQ1 sensitivity by IDH1 mutation seems to be specific for ICC cells. Our findings propose a new stratified therapeutic strategy based on IDH1 mutation in ICC.

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

“…While there is a paucity of research on RNA methylation status as a therapeutic target, histone-modifying agents such as histone deacetylase inhibitors and histone methyltransferase inhibitors are already in phase 1/2 clinical testing for AML, glioma, cholangiocarcinoma, and myelodysplastic syndromes (126–129). Early preclinical data in intrahepatic cholangiocarcinoma in particular suggests that bromodomain and extraterminal domain (BET) (histone regulatory complexes) inhibitors such as JQ1 may have an enhanced antiproliferative effect in IDH-mutant cancer cell lines (130). Furthermore, downstream oncogenic effects of histone dysregulation in IDH-mutant cancers, such as downregulation of the ATM gene causing an increase in spontaneous DNA damage, continue to become more well understood and suggest that a parallel effort to understand and target epigenetic memory carried in histones, in addition to DNA methylation, should be pursued (131).…”

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

“…Interestingly, Fujiwara H et al reported that AML patients with IDH mutations had a 14-fold higher response rate to BET inhibitors than common patients. 491 The combination strategy of IDH inhibitors with the DNMT inhibitor azacitidine in AML treatment has also been evaluated in several clinical trials, and the preliminary results are encouraging. 492,493 In addition to EZH2, HDAC, and IDH inhibitors, targeting DNMT is also a potential strategy for cancer therapy.…”

BRD4: An emerging prospective therapeutic target in glioma

“…However, in other models, for example AML or cholangiocarcinoma, IDH mutant cancer cells showed a better response rate to BRD4 inhibitors. 69 , 70 …”