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AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis

Dae Gyu Kim1, Yongseok Choi2, Yuno Lee3

  • 1Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, Korea.

Nature Communications
|May 13, 2022
PubMed

Insights

A tumor suppressor variant, AIMP2-DX2, enhances KRAS-driven cancers by stabilizing KRAS. Inhibiting the AIMP2-DX2 and KRAS interaction with a novel molecule suppresses tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Oncogenic KRAS mutations drive cancer, and targeted inhibitors are of significant interest.
  • AIMP2-DX2, a variant of the tumor suppressor AIMP2, influences cancer progression.

Purpose of the Study:

  • To investigate the role of AIMP2-DX2 in regulating KRAS stability and KRAS-driven tumorigenesis.
  • To identify therapeutic strategies targeting the AIMP2-DX2-KRAS interaction.

Main Methods:

  • Investigated AIMP2-DX2 binding to KRAS and its effect on KRAS stability.
  • Examined the competitive inhibition of Smurf2 access to KRAS by AIMP2-DX2.
  • Correlated AIMP2-DX2 and KRAS levels in cancer cell lines and tissues.
  • Identified and tested a small molecule inhibitor of the AIMP2-DX2-KRAS interaction in vitro and in vivo.

Main Results:

  • AIMP2-DX2 binds to KRAS, preventing Smurf2-mediated degradation and enhancing KRAS stability.
  • AIMP2-DX2 levels positively correlate with KRAS levels in colon and lung cancers.
  • A novel small molecule inhibitor targeting the AIMP2-DX2-KRAS interface reduced KRAS levels and suppressed cancer cell growth.

Conclusions:

  • AIMP2-DX2 acts as a cancer-specific regulator, augmenting KRAS-driven tumorigenesis by stabilizing KRAS.
  • The AIMP2-DX2-KRAS interaction interface represents a promising therapeutic target for controlling KRAS-driven cancers.

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