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

  • Oncogene. 2026 Jul;45(28):2808-2822. doi: 10.1038/s41388-026-03838-1.
Yanjing Zhu  #  1  2 ,  Chi Zhang  #  1  2 ,  Min Li  #  2 ,  Luoyan Ai  #  1  2 ,  Fan Xu  2 ,  Yiyi Yu  1  2 ,  Shan Yu  1  2 ,  Xiaojing Xu  1  2 ,  Qing Liu  1  2 ,  Mengxuan Zhu  1  2 ,  Mengling Liu  1  2 ,  Jingyuan Wang  1  2 ,  Yutong Liu  1  2 ,  Zhenghang Xu  1  2 ,  Haojie Zhou  1  2 ,  Huishan Li  1  2 ,  Rui Wu  3 ,  Ke Peng  4  5 ,  Tianshu Liu  6  7  8  9  10
Affiliations
  • 1. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Cancer Center, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medicine School, Nanjing University, Nanjing, China. [email protected].
  • 4. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 5. Cancer Center, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 6. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 7. Cancer Center, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 8. Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. [email protected].
  • 9. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen, China. [email protected].
  • 10. Center of Evidence-based Medicine, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42270775 DOI: 10.1038/s41388-026-03838-1
Abstract

Despite substantial advances in targeting KRASG12C, tumor acquired resistance to KRASG12C inhibitors (KRASG12Ci) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergence point of KRASG12Ci resistance. Multi-omics profiling of resistant models revealed a chronic activation of the integrated stress response (ISR) and a concomitant upregulation of asparagine synthesis. We found that the ISR-inducible transcription factor ATF3 was upregulated and directly transactivated asparagine synthetase (ASNS), driving asparagine production. Genetic ablation of ATF3 or ASNS restored KRASG12Ci sensitivity, whereas exogenous asparagine reconstituted resistance. This ATF3-ASNS axis was conserved in the patient-derived model of acquired KRASG12Ci resistance. Furthermore, pharmacological inhibition of the upstream ISR kinase PERK synergized with KRASG12Ci to overcome resistance. This study reveals a therapeutically targetable mechanism of asparagine metabolic reprogramming that facilitates KRASG12C inhibitor resistance.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    Sotorasib
    99.70%, KRAS G12C Inhibitor
    target: Ras
    Research Areas: Cancer