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

Chi Chun Wong1, Jian-Lin Wu2, Fenfen Ji3

  • 1Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. chichunwong@cuhk.edu.hk.

Nature Communications
|July 8, 2022
PubMed

Insights

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) drives KRAS-mutant colorectal cancer (CRC) by boosting cholesterol synthesis and KRAS activation. Inhibiting PCSK9 offers a potential therapeutic strategy for this challenging cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • KRAS-mutant colorectal cancer (CRC) presents a significant therapeutic challenge.
  • Targeting KRAS-mutant CRC remains an unmet clinical need.

Purpose of the Study:

  • To investigate the role of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) in APC/KRAS-mutant CRC.
  • To determine if PCSK9 is a viable therapeutic target for KRAS-mutant CRC.

Main Methods:

  • Analysis of CRC patient cohorts, isogenic cell lines, and transgenic mouse models.
  • Assessment of cholesterol biosynthesis, geranylgeranyl diphosphate (GGPP) levels, and KRAS activation.
  • Evaluation of PCSK9 inhibitors and simvastatin in preclinical CRC models.

Main Results:

  • PCSK9 is upregulated in APC/KRAS-mutant CRC, correlating with increased de novo cholesterol biosynthesis and GGPP accumulation.
  • PCSK9 depletion inhibits, while overexpression promotes, CRC cell growth.
  • PCSK9 activates KRAS/MEK/ERK signaling via GGPP.
  • PCSK9 inhibitors, particularly with simvastatin, suppress tumor growth.

Conclusions:

  • PCSK9 promotes APC/KRAS-mutant CRC progression through the GGPP-KRAS/MEK/ERK pathway.
  • PCSK9 is a promising therapeutic target for KRAS-mutant CRC.
  • High PCSK9 expression is associated with poor patient survival.

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