Open AccessTargeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression
Author(s) -
Chong Yong Chun,
Toh Tan Boon,
Chan Zhiling,
Lin Quy Xiao Xuan,
Thng Dexter Kai Hao,
Hooi Lissa,
Ding Zhaobing,
Shuen Timothy,
Toh Han Chong,
Dan Yock Young,
Bonney Glenn Kunnath,
Zhou Lei,
Chow Pierce,
Wang Yulan,
Benoukraf Touati,
Chow Edward KaiHua,
Han Weiping
Publication year - 2020
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1559
Subject(s) - cancer research , biology , carcinogenesis , purine metabolism , gene knockdown , cancer , kinome , pi3k/akt/mtor pathway , purine , kinase , signal transduction , biochemistry , enzyme , apoptosis , genetics
We demonstrate that in human HCCs with deregulated expression of purine metabolic enzymes, targeting purine metabolism was effective in blocking tumor cell proliferation, leading to tumor shrinkage. Precise regulation of purine metabolic activity was coordinated by the activation status of a PI3K‐E2F1 axis, and potent suppression of purine metabolism via combinatorial targeting of PI3K and the purine synthetic rate‐limiting enzyme IMPDH resulted in enhanced efficacy in a pre‐clinical model. These data provide a strong basis for future precision‐medicine focused clinical trials targeting this tumor‐specific metabolic adaptation as a point of vulnerability in patients with HCC.