Chi Chun Wong, Jian-Lin Wu, Fenfen Ji, Wei Kang, Xiqing Bian, Huarong Chen, Lam-Shing Chan, Simson Tsz Yat Luk, Samuel Tong, Jiaying Xu, Qiming Zhou, Dabin Liu, Hao Su, Hongyan Gou, Alvin Ho-Kwan Cheung, Ka Fai To, Zongwei Cai, Jerry W Shay, Jun Yu
Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de novo cholesterol biosynthesis is induced in APC/KRAS mutant CRC, accompanied by increased geranylgeranyl diphosphate (GGPP)─a metabolite necessary for KRAS activation. PCSK9 is the top up-regulated cholesterol-related gene...
July 8, 2022: Nature Communications