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Adv."],"published-print":{"date-parts":[[2026,10,23]]},"abstract":"<jats:p>\n                    CASTOR1, a cytosolic arginine sensor and regulator of mTORC1 signaling, is identified here as a tumor suppressor in\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    -driven non\u2013small cell lung cancer (NSCLC). In a\n                    <jats:italic toggle=\"yes\">\n                      KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model,\n                    <jats:italic toggle=\"yes\">CASTOR1<\/jats:italic>\n                    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 KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    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\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    -driven NSCLC progression and therapeutic resistance. The results further support rational combination therapies to overcome KRAS inhibitor resistance in CASTOR1-low NSCLC.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb9836","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T17:58:42Z","timestamp":1792778322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["<i>CASTOR1<\/i>\n                    functional inactivation drives\n                    <i>KRAS<\/i>\n                    -mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-7229","authenticated-orcid":true,"given":"Xian","family":"Wang","sequence":"first","affiliation":[{"name":"Cancer Virology Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh 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