生物
癌症研究
蛋白激酶A
融合基因
融合蛋白
蛋白质亚单位
肝细胞癌
激酶
基因
细胞生物学
生物化学
重组DNA
作者
Akiko Toyota,Megumi Goto,Masaharu Miyamoto,Yoko Nagashima,Shiho Iwasaki,Takahiro Komatsu,T. Momose,Keisuke Yoshida,Tomoharu Tsukada,Tetsuyoshi Matsufuji,Ami Ohno,Makoto Suzuki,Osamu Ubukata,Yasuyuki Kaneta
标识
DOI:10.1016/j.bbrc.2022.07.008
摘要
Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC. It has also been reported that PRKACA kinase activity is essential for its oncogenic activity, suggesting that PRKACA kinase inhibition could be considered as an useful therapeutic target. In this study, we established an evaluation system for PRKACA kinase inhibitors and synthesized DS89002333, a novel PRKACA inhibitor. DS89002333 showed potent PRKACA inhibitory activity and inhibited fusion protein-dependent cell growth both in vitro and in vivo. Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.
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