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Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation

Tonci Ivanisevic1, Yan Ma1, Emiel Van Boxel1,2

  • 1VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.

Nature Communications
|December 15, 2025
PubMed

Insights

Elevated wild-type KRAS (WT-KRAS) protein drives resistance to lung cancer therapies. Impaired degradation of WT-KRAS activates pathways that can be targeted to restore sensitivity to KRAS inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Activating KRAS mutations are common in lung adenocarcinoma (LUAD).
  • Intrinsic resistance limits the efficacy of RAS-targeted therapies in KRAS-mutant LUAD.
  • Understanding resistance mechanisms is crucial for improving LUAD treatment outcomes.

Purpose of the Study:

  • To identify key drivers of intrinsic resistance in KRAS-mutant lung tumors.
  • To elucidate the molecular mechanisms underlying WT-KRAS accumulation and its role in therapeutic resistance.
  • To explore novel therapeutic strategies for overcoming resistance to RAS inhibitors.

Main Methods:

  • Analysis of KRAS protein levels and LZTR1 function in LUAD models.
  • Investigating the role of WT-KRAS in activating the mTOR/HIF1α pathway.
  • Utilizing in vitro and in vivo models to assess the efficacy of combinatorial therapies.

Main Results:

  • Elevated WT-KRAS protein, due to impaired LZTR1-mediated degradation, was identified as a driver of intrinsic resistance.
  • Stabilized WT-KRAS activates the mTOR/HIF1α pathway by altering lysosomal amino acid sensing.
  • Shallow LZTR1 deletions correlate with increased mTOR activity and resistance to RAS inhibitors.
  • Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex restored sensitivity to KRAS inhibitors.

Conclusions:

  • WT-KRAS accumulation is a significant mechanism of intrinsic resistance in KRAS-mutant lung cancer.
  • Targeting mTOR signaling or amino acid transport offers a promising strategy to overcome resistance.
  • Combinatorial therapies hold potential for improving long-term efficacy of RAS inhibitors in LUAD.

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