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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions

Published on: May 27, 2021

DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer

Jun Liang1, Xi Liu1, Ziyun Ni1

  • 1Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.

Cell Reports
|July 24, 2026
PubMed

Insights

Dihydroorotate dehydrogenase (DHODH) is a key metabolic dependency in PIK3CA-mutant colorectal cancer (CRC). Inhibiting DHODH disrupts cancer cell signaling and growth, offering a potential therapeutic strategy for CRC.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Cancer cells exhibit unique metabolic and signaling dependencies driven by oncogenic mutations.
  • Identifying these mutation-specific vulnerabilities is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify dihydroorotate dehydrogenase (DHODH) as a selective metabolic dependency in PIK3CA-mutant colorectal cancer (CRC).
  • To elucidate the mechanism by which DHODH supports cancer cell signaling and self-renewal.

Main Methods:

  • Investigated DHODH dependency in PIK3CA-mutant CRC cells.
  • Utilized genetic and pharmacological inhibition of DHODH.
  • Assessed WDR77 O-GlcNAcylation, AKT signaling, and cancer cell self-renewal.
  • Employed uridine supplementation and O-GlcNAc transferase (OGT) depletion experiments.
  • Evaluated the efficacy of DHODH inhibitor HL6 in various CRC models.

Main Results:

  • DHODH was identified as a selective metabolic dependency in PIK3CA-mutant CRC.
  • DHODH inhibition reduced WDR77 protein levels, decreased AKT phosphorylation, and impaired cancer cell self-renewal and tumor initiation.
  • Uridine supplementation rescued WDR77 and AKT signaling, dependent on OGT activity.
  • The DHODH inhibitor HL6 suppressed tumor growth in preclinical CRC models.

Conclusions:

  • Metabolic regulation of protein stability is a critical mechanism underlying oncogene-specific dependencies in CRC.
  • DHODH inhibition represents a promising therapeutic strategy for PIK3CA-mutant colorectal cancer.
Keywords:
CP: cancerDHODHO-GlcNAcylationPIK3CA mutationcancer stemnesscolorectal cancer

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