{
  "abstract": "Acquired resistance to epidermal growth factor receptor (EGFR)-targeted therapy remains a major obstacle in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). This study investigated whether repurposing mebendazole (MBZ), a microtubule-disrupting agent, could restore sensitivity to gefitinib in gefitinib-resistant HCC827 GR5 cells. Gefitinib monotherapy showed minimal cytotoxicity, reducing cell viability only marginally (92.7 ± 1.5%), whereas MBZ significantly decreased viability to 79.7 ± 0.6% at 0.1 µM and 29.7 ± 0.6% at 0.5 µM (p < 0.001). Combination treatment (gefitinib 1 µM + MBZ 0.1 µM) further reduced viability to 37.7 ± 0.6% (p < 0.001). Mechanistically, alkaline comet assay revealed significantly increased single-strand DNA damage in the combination group (tail intensity 22.33 ± 0.56%, p < 0.001), while neutral comet assay confirmed elevated double-strand DNA breaks. MBZ also induced dose-dependent γ-H2AX activation (p < 0.001), supporting replication stress-associated DNA damage signaling. In vivo, combination therapy significantly suppressed tumor growth, prolonging tumor doubling time from 6.2 days in controls to 25 days and increasing growth delay to 18.8 days (p < 0.01), without substantial systemic toxicity. Collectively, these findings identify replication stress vulnerability as a therapeutically exploitable axis and support MBZ repurposing as an adjuvant strategy to overcome gefitinib resistance.",
  "abstract_shown": true,
  "affiliations": [
    "RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates",
    "Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates",
    "Department of Perfusion Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India",
    "Royal Cornwall Hospital Trust, NHS, Truro, United Kingdom",
    "Department School of Chemistry and Biomedical Sciences, University of Bradford, Bradford, United Kingdom"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Mohamed El-Tanani"
    },
    {
      "affs": [
        1
      ],
      "name": "Shakta Mani Satyam"
    },
    {
      "affs": [
        2
      ],
      "name": "Sainath Prabhakar"
    },
    {
      "affs": [
        3
      ],
      "name": "Yahia El-Tanani"
    },
    {
      "affs": [
        4
      ],
      "name": "Ebrahim Safaii"
    },
    {
      "name": "Syed Arman Rabbani"
    },
    {
      "name": "Mark Sutherland"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/am0ghwnnavb0t.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0360164",
  "fulltext_url": null,
  "id": "am0ghwnnavb0t",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0360164",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA damage"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA replication"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cytoskeleton/Microtubules"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/EGFR signaling"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/Stress signaling cascade"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/DNA/DNA damage"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/DNA/DNA replication"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancer treatment"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Lung and intrathoracic tumors/Non-small cell lung cancer"
    ]
  ],
  "openalex": "W7220932764",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0360164&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-08",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/am0ghwnnavb0t.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.pone.0360164",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0360164"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    },
    {
      "field": "medicine",
      "origin": "plos:oncology",
      "subfield": "oncology"
    }
  ],
  "title": "Dual targeting of EGFR signaling and microtubule dynamics enhances replication-associated cellular stress and suppresses tumor growth in gefitinib-resistant non-small cell lung cancer",
  "title_text": "Dual targeting of EGFR signaling and microtubule dynamics enhances replication-associated cellular stress and suppresses tumor growth in gefitinib-resistant non-small cell lung cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:30Z",
  "url": "https://research.draconitic.com/paper/am0ghwnnavb0t",
  "venue": "PLOS One",
  "versions": []
}