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Updated: Jun 30, 2025

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Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small

Xiameng Gai1,2, Yingluo Liu2, Xiaojing Lan2,3

  • 1School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, China.

Cancer Research
|March 19, 2024
PubMed

Insights

Oncogenic KRAS in lung cancer silences ASS1, an enzyme crucial for arginine production. This creates a dependency on arginine uptake via SLC7A1, offering a new therapeutic target for KRAS-mutant non-small cell lung cancer.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • The urea cycle is often reprogrammed in cancer cells to support their metabolic needs.
  • Understanding how oncogenic signaling alters the urea cycle can reveal metabolic vulnerabilities in cancer.

Purpose of the Study:

  • To investigate the mechanism by which oncogenic KRAS signaling affects urea cycle metabolism in non-small cell lung cancer (NSCLC).
  • To identify potential therapeutic targets based on metabolic alterations in KRAS-mutant NSCLC.

Main Methods:

  • Analysis of KRAS signaling pathways in NSCLC.
  • Investigation of histone modifications and transcription factor recruitment at the ASS1 gene promoter.
  • Assessment of arginine biosynthesis and uptake in cancer cells.
  • Evaluation of SLC7A1 inhibition in patient-derived organoid and xenograft models.

Main Results:

  • Oncogenic KRAS activation in NSCLC leads to the silencing of argininosuccinate synthase 1 (ASS1) expression.
  • KRAS signaling induces a hypoacetylated state at the ASS1 promoter via histone deacetylase 3 (HDAC3), preventing c-MYC binding and transcription.
  • ASS1 suppression impairs arginine biosynthesis, making KRAS-mutant NSCLC cells dependent on extracellular arginine uptake mediated by SLC7A1.
  • Inhibition of SLC7A1 significantly suppressed tumor growth in preclinical models of KRAS-driven NSCLC.

Conclusions:

  • Oncogenic KRAS rewires urea cycle metabolism in NSCLC by downregulating ASS1.
  • This metabolic reprogramming creates a dependency on SLC7A1 for arginine import.
  • Targeting SLC7A1-mediated arginine uptake represents a promising therapeutic strategy for KRAS-mutant NSCLC.

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