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Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASG12C inhibitors

Yanjing Zhu1,2, Chi Zhang1,2, Min Li2

  • 1Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

Oncogene
|June 10, 2026
PubMed

Insights

Acquired resistance to KRAS inhibitors is driven by ATF3-mediated asparagine synthesis. Targeting this pathway, alongside KRAS inhibitors, may overcome resistance in cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Reprogramming

Background:

  • Targeting KRAS G12C mutations shows promise in cancer therapy.
  • Acquired resistance to KRAS G12C inhibitors (KRAS G12C i) is a significant clinical challenge.

Purpose of the Study:

  • To identify the molecular mechanisms underlying acquired resistance to KRAS G12C inhibitors.
  • To explore ATF3-driven metabolic reprogramming as a resistance mechanism.

Main Methods:

  • Multi-omics profiling of resistant cancer models.
  • Genetic ablation of ATF3 and asparagine synthetase (ASNS).
  • Pharmacological inhibition of the integrated stress response (ISR) kinase PERK.

Main Results:

  • Resistant models exhibit chronic ISR activation and increased asparagine synthesis.
  • ATF3 directly upregulates ASNS, driving asparagine production and resistance.
  • Genetic or pharmacological targeting of the ATF3-ASNS axis restores sensitivity to KRAS G12C i.
  • PERK inhibition synergizes with KRAS G12C i to overcome resistance.

Conclusions:

  • ATF3-driven asparagine metabolic reprogramming is a key mechanism of KRAS G12C i resistance.
  • The ATF3-ASNS axis represents a novel therapeutic vulnerability in KRAS G12C -mutant cancers.
  • Inhibition of the ISR pathway offers a potential strategy to overcome KRAS G12C i resistance.

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