{
  "abstract": "Background\n\nT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with poor prognosis, especially in relapsed/refractory patients. Aberrant PI3K/AKT/mTOR and NOTCH1 signaling converge on c-MYC to drive proliferation and ribosome biogenesis, but single-agent inhibitors targeting these pathways have shown limited clinical efficacy.Methods\n\nAn FDA-approved drug library screen identified osimertinib as a candidate anti-T-ALL agent. Its efficacy and mechanism were evaluated in four T-ALL cell lines (MOLT-4, Jurkat, CCRF/CEM, and MOLT-3) with different TP53 statuses and in primary T-ALL blasts. Combination studies with selinexor, an exportin 1 (XPO1) inhibitor, were performed. Multi-omics, biochemical, and functional assays were used, and efficacy and toxicity were assessed in T-ALL xenograft models.Results\n\nOsimertinib suppressed leukemic progression in vivo by promoting proteasome-dependent degradation of c-MYC through a non-canonical, EGFR-independent pathway that cannot be fully explained by inhibition of PI3K/AKT/mTOR or NOTCH1 signaling alone. This c-MYC suppression impaired ribosome biogenesis, and combining osimertinib with selinexor further disrupted this process. The combination increased apoptosis at low concentrations (0.5-2 µM osimertinib plus 20 nM selinexor), with clear synergy at 2 µM in all four T-ALL cell lines. Mechanistically, the combination caused nuclear retention of RPS6, nuclear accumulation of RPL5/RPL11, nucleolar stress (fibrillarin dispersal), decreased MDM2 protein levels, p53 stabilization, BAX activation (6A7), cytochrome c release, c-MYC depletion, and translational suppression. In vivo, the combination improved survival and reduced leukemic burden with minimal toxicity to normal cells at low doses. Potential biomarkers include c-MYC dependency and TP53 status as candidate stratification factors, and treatment-induced c-MYC depletion and RPL5/RPL11 nuclear accumulation as candidate pharmacodynamic biomarkers.Conclusions\n\nOsimertinib plus selinexor depletes c-MYC, induces nucleolar stress, and suppresses translation, which together drive T-ALL cell apoptosis. This mechanism-driven combination shows preclinical efficacy with limited toxicity in the normal-cell and xenograft models tested. Further studies incorporating pharmacokinetic monitoring, PDX models, and prospective validation of candidate biomarkers such as c-MYC dependency, TP53 status, and RPL5/RPL11 nuclear accumulation are warranted before clinical translation.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Hematology, Daping Hospital (Army Medical Center of PLA), Army Medical University (Third Military Medical University), Chongqing, China.",
    "Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China.",
    "Center for Hematology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.",
    "Center for Hematology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China. xushuangnian@tmmu.edu.cn.",
    "Department of Hematology, Daping Hospital (Army Medical Center of PLA), Army Medical University (Third Military Medical University), Chongqing, China. lixi1988@tmmu.edu.cn.",
    "Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China. lixi1988@tmmu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Rushuang Xu"
    },
    {
      "affs": [
        2
      ],
      "name": "Xiangtao Huang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jia Liu"
    },
    {
      "affs": [
        2
      ],
      "name": "Yingying Shang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Na Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiegang Xu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shidi Cheng"
    },
    {
      "affs": [
        3
      ],
      "name": "Shuangnian Xu"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Xi Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7ff9vq8a9v6dk.bib",
  "cited_by": 0,
  "doi": "10.1186/s40364-026-01031-w",
  "fulltext_url": "https://europepmc.org/articles/PMC13718067",
  "id": "7ff9vq8a9v6dk",
  "issns": [
    "2050-7771"
  ],
  "landing_url": "https://europepmc.org/article/MED/42958372",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2739|Acute Lymphoblastic Leukemia research"
    ]
  ],
  "openalex": "W7224251825",
  "pdf_url": "https://europepmc.org/articles/PMC13718067?pdf=render",
  "pmcid": "PMC13718067",
  "pmid": "42958372",
  "published": "2026-10-28",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/7ff9vq8a9v6dk.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:36Z",
      "native_id": "MED:42958372",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42958372"
    },
    {
      "first_seen": "2026-11-02T12:22:13Z",
      "native_id": "PMC13718067",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s40364-026-01031-w"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2739|Acute Lymphoblastic Leukemia research",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia.",
  "title_text": "Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:22:13Z",
  "url": "https://research.draconitic.com/paper/7ff9vq8a9v6dk",
  "venue": "Biomarker research",
  "versions": []
}