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Peer-reviewedCC BY-NCScience Advances

CASTOR1 functional inactivation drives KRAS -mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression

  • Xian Wang1,2
  • Ling Ding1,2
  • Wen Meng1,2
  • Elaine Byrnes3
  • Suet Kee Loo1,2
  • Shenyu Sun1,2
  • Luping Chen1,2
  • Tingting Li1,2
  • Man-Tzu Wang4
  • Arjun Pennathur3
  • Yufei Huang1,5
  • Shou-Jiang Gao1,2
5 affiliations
  1. 1Cancer Virology Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
  2. 2Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  3. 3Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  4. 4Cancer Biology Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
  5. 5Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
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Abstract

CASTOR1, a cytosolic arginine sensor and regulator of mTORC1 signaling, is identified here as a tumor suppressor in KRAS-driven non-small cell lung cancer (NSCLC). In a KRASG12D mouse model, CASTOR1 deletion enhances tumor initiation and progression, accompanied by increased proliferation. Although CASTOR1 is rarely mutated or deleted in human cancers, its expression progressively declines during tumor progression and is associated with increased AKT activation and CASTOR1 phosphorylation, consistent with functional inactivation. Loss of CASTOR1 results in constitutive mTORC1 hyperactivation, impaired arginine-dependent regulation of mTORC1 signaling, elevated p-4EBP1 and p-S6 levels, increased AKT and ERK activation, genomic instability, and resistance to KRASG12D inhibitors. Tumors and tumor-derived organoids deficient in CASTOR1 are resistant to KRAS inhibition, but this resistance can be overcome by cotargeting mTORC1 or dual PI3K/mTOR inhibition. These findings identify CASTOR1 as a critical link between nutrient sensing and oncogenic signaling and reveal its functional inactivation as an important mechanism contributing to KRAS-driven NSCLC progression and therapeutic resistance. The results further support rational combination therapies to overcome KRAS inhibitor resistance in CASTOR1-low NSCLC.

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Cite

BibTeXRIS
BibTeX
@article{wang2026castor1,
  title = {{CASTOR1 functional inactivation drives KRAS -mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression}},
  author = {Xian Wang and Ling Ding and Wen Meng and Elaine Byrnes and Suet Kee Loo and Shenyu Sun and Luping Chen and Tingting Li and Man-Tzu Wang and Arjun Pennathur and Yufei Huang and Shou-Jiang Gao},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeb9836},
  url = {https://www.science.org/doi/10.1126/sciadv.aeb9836},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - CASTOR1 functional inactivation drives KRAS -mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression
AU  - Xian Wang
AU  - Ling Ding
AU  - Wen Meng
AU  - Elaine Byrnes
AU  - Suet Kee Loo
AU  - Shenyu Sun
AU  - Luping Chen
AU  - Tingting Li
AU  - Man-Tzu Wang
AU  - Arjun Pennathur
AU  - Yufei Huang
AU  - Shou-Jiang Gao
PY  - 2026
DA  - 2026/10/23
JO  - Science Advances
DO  - 10.1126/sciadv.aeb9836
UR  - https://www.science.org/doi/10.1126/sciadv.aeb9836
AB  - CASTOR1, a cytosolic arginine sensor and regulator of mTORC1 signaling, is identified here as a tumor suppressor in KRAS-driven non-small cell lung cancer (NSCLC). In a KRASG12D mouse model, CASTOR1 deletion enhances tumor initiation and progression, accompanied by increased proliferation. Although CASTOR1 is rarely mutated or deleted in human cancers, its expression progressively declines during tumor progression and is associated with increased AKT activation and CASTOR1 phosphorylation, consistent with functional inactivation. Loss of CASTOR1 results in constitutive mTORC1 hyperactivation, impaired arginine-dependent regulation of mTORC1 signaling, elevated p-4EBP1 and p-S6 levels, increased AKT and ERK activation, genomic instability, and resistance to KRASG12D inhibitors. Tumors and tumor-derived organoids deficient in CASTOR1 are resistant to KRAS inhibition, but this resistance can be overcome by cotargeting mTORC1 or dual PI3K/mTOR inhibition. These findings identify CASTOR1 as a critical link between nutrient sensing and oncogenic signaling and reveal its functional inactivation as an important mechanism contributing to KRAS-driven NSCLC progression and therapeutic resistance. The results further support rational combination therapies to overcome KRAS inhibitor resistance in CASTOR1-low NSCLC.
SN  - 2375-2548
ER  -