{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Cancer Virology Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.",
    "Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.",
    "Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.",
    "Cancer Biology Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.",
    "Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Xian Wang",
      "orcid": "0000-0001-7679-7229"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ling Ding",
      "orcid": "0000-0002-8105-3248"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Wen Meng",
      "orcid": "0000-0001-6771-0881"
    },
    {
      "affs": [
        2
      ],
      "name": "Elaine Byrnes"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Suet Kee Loo",
      "orcid": "0000-0002-4558-1967"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shenyu Sun"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Luping Chen"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tingting Li"
    },
    {
      "affs": [
        3
      ],
      "name": "Man-Tzu Wang",
      "orcid": "0000-0003-4780-173X"
    },
    {
      "affs": [
        2
      ],
      "name": "Arjun Pennathur",
      "orcid": "0000-0001-7937-7991"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Yufei Huang",
      "orcid": "0000-0001-6268-5357"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shou-Jiang Gao",
      "orcid": "0000-0001-6194-1742"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bzz9g2fvg4x6k.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aeb9836",
  "fulltext_url": "https://europepmc.org/articles/PMC13693695",
  "id": "bzz9g2fvg4x6k",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aeb9836",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|PI3K/AKT/mTOR signaling in cancer"
    ]
  ],
  "openalex": "W7223292370",
  "pdf_url": "https://europepmc.org/articles/PMC13693695?pdf=render",
  "pmcid": "PMC13693695",
  "pmid": "42913021",
  "published": "2026-10-23",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/bzz9g2fvg4x6k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aeb9836",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aeb9836"
    },
    {
      "first_seen": "2026-10-30T12:20:03Z",
      "native_id": "MED:42913021",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42913021"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|PI3K/AKT/mTOR signaling in cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "CASTOR1 functional inactivation drives KRAS -mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression",
  "title_text": "CASTOR1 functional inactivation drives KRAS -mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:03Z",
  "url": "https://research.draconitic.com/paper/bzz9g2fvg4x6k",
  "venue": "Science Advances",
  "versions": []
}