The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

Chi Chun Wong(Chinese University of Hong Kong), Jian‐Lin Wu(Macau University of Science and Technology), Fenfen Ji(Chinese University of Hong Kong), Wei Kang(Chinese University of Hong Kong), Xiqing Bian(Macau University of Science and Technology), Huarong Chen(Chinese University of Hong Kong), Lam-Shing Chan(Chinese University of Hong Kong), Simson Tsz Yat Luk(Chinese University of Hong Kong), Samuel Tong(Chinese University of Hong Kong), Jiaying Xu(Chinese University of Hong Kong), Qiming Zhou(Chinese University of Hong Kong), Dabin Liu(Chinese University of Hong Kong), Hao Su(Chinese University of Hong Kong), Hongyan Gou(Chinese University of Hong Kong), Alvin H.K. Cheung(Chinese University of Hong Kong), Ka‐Fai To(Chinese University of Hong Kong), Zongwei Cai(Hong Kong Baptist University), Jerry W. Shay(The University of Texas Southwestern Medical Center), Jun Yu(Chinese University of Hong Kong)
Nature Communications
July 8, 2022
10.1038/s41467-022-31663-z
Cited by 94Open Access
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Abstract

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. PCSK9 depletion represses APC/KRAS-mutant CRC cell growth in vitro and in vivo, whereas PCSK9 overexpression induces oncogenesis. Mechanistically, PCSK9 reduces cholesterol uptake but induces cholesterol de novo biosynthesis and GGPP accumulation. GGPP is a pivotal metabolite downstream of PCSK9 by activating KRAS/MEK/ERK signaling. PCSK9 inhibitors suppress growth of APC/KRAS-mutant CRC cells, organoids and xenografts, especially in combination with simvastatin. PCSK9 overexpression predicts poor survival of APC/KRAS-mutant CRC patients. Together, cholesterol homeostasis regulator PCSK9 promotes APC/KRAS-mutant CRC via GGPP-KRAS/MEK/ERK axis and is a therapeutic target.

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