2. Academic Validation
  3. Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation

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

  • Nat Commun. 2025 Dec 15. doi: 10.1038/s41467-025-67109-5.
Tonci Ivanisevic # 1,  Yan Ma # 1,  Emiel Van Boxel 1 2,  Wout Magits 1,  Benoit Lechat 1,  Zeynep Koçberber 3 4,  Phillipp Willnow 3 4,  Sarah-Maria Fendt 3 4,  Greetje Vande Velde 5 6,  Raj Sewduth 7,  Anna A Sablina 8 9
Affiliations

Affiliations

  • 1 VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
  • 2 Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • 3 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
  • 4 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • 5 Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
  • 6 Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
  • 7 VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium. [email protected].
  • 8 VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium. [email protected].
  • 9 Department of Oncology, KU Leuven, Leuven, Belgium. [email protected].
  • # Contributed equally.
PMID: 41397976 DOI: 10.1038/s41467-025-67109-5
Abstract

Activating mutations in KRAS occur in approximately 30% of lung adenocarcinomas. Despite advances in RAS-targeted therapies, intrinsic resistance limits their long-term efficacy. Here, we identify elevated levels of wild-type KRAS (WT-KRAS) protein as a key driver of intrinsic resistance in KRAS-mutant lung tumors. KRAS accumulation results from impaired LZTR1-mediated degradation, triggered either by LZTR1 loss or pharmacological Ras inhibition. Stabilized WT-KRAS activates the mTOR/HIF1α pathway by promoting lysosomal recruitment of the SLC3A2/SLC7A5 Amino acid Transporter complex, reprogramming lysosomal amino acid sensing. Shallow deletions of LZTR1, present in up to 40% of KRAS-mutant lung adenocarcinomas, are associated with increased mTOR activity and may contribute to therapeutic resistance to Ras inhibitors. Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung Cancer.

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