Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
1/5 보강
Activating mutations in KRAS occur in approximately 30% of lung adenocarcinomas.
APA
Ivanisevic T, Ma Y, et al. (2025). Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.. Nature communications, 17(1), 411. https://doi.org/10.1038/s41467-025-67109-5
MLA
Ivanisevic T, et al.. "Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.." Nature communications, vol. 17, no. 1, 2025, pp. 411.
PMID
41397976 ↗
Abstract 한글 요약
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.
🏷️ 키워드 / MeSH 📖 같은 키워드 OA만
- Proto-Oncogene Proteins p21(ras)
- Humans
- Lung Neoplasms
- Drug Resistance
- Neoplasm
- TOR Serine-Threonine Kinases
- Animals
- Cell Line
- Tumor
- Mice
- Signal Transduction
- Adenocarcinoma of Lung
- Hypoxia-Inducible Factor 1
- alpha Subunit
- Mutation
- Proteolysis
- Lysosomes
- Amino Acid Transport Systems
- Basic
- Minor Histocompatibility Antigens
- Amino Acid Transport System A
- Female
- Fusion Regulatory Protein 1
- Heavy Chain
… 외 1개
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