{
  "abstract": "Introduction: Acquired resistance to osimertinib remains a major challenge in the treatment of EGFR-mutant lung adenocarcinoma (LUAD), yet the contribution of stress-responsive protein homeostasis to resistance remains incompletely understood. This study aimed to investigate the role and regulatory mechanisms of ankyrin repeat domain 1 (ANKRD1) in acquired osimertinib resistance.\n\nMethods: Public transcriptomic datasets and machine learning-based feature selection were integrated with osimertinib-resistant LUAD cell models, paired clinical specimens, RNA sequencing, biochemical and molecular assays, functional rescue experiments, and in vivo tumor models to investigate the role of ANKRD1 and its upstream and downstream regulatory mechanisms in osimertinib resistance.\n\nResults: ANKRD1 was upregulated in osimertinib-resistant LUAD models and promoted tumor cell survival under therapeutic pressure. Mechanistically, zinc finger protein 593 (ZNF593) interacted with ANKRD1 and facilitated its SUMO1-dependent modification, which was associated with reduced ubiquitin-mediated degradation and enhanced ANKRD1 protein stability. Stabilized ANKRD1 subsequently promoted MERTK expression and sustained downstream AKT signaling, thereby supporting tumor cell survival under osimertinib pressure. Furthermore, K41 emerged as a critical regulatory residue, as K41R simultaneously impaired ANKRD1 SUMOylation, ubiquitination, and interaction with ZNF593, accompanied by attenuated downstream signaling and resistance phenotypes. These findings suggest that K41 plays an important role in coordinating ANKRD1 post-translational regulation and its interaction with ZNF593.\n\nDiscussion: Our study identifies a proteostasis-related mechanism contributing to acquired osimertinib resistance and provides mechanistic insight into the ZNF593–ANKRD1–MERTK axis in EGFR-mutant LUAD. These findings support further investigation of this regulatory axis as a potential vulnerability in osimertinib-resistant LUAD.",
  "abstract_shown": true,
  "affiliations": [
    "The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center",
    "West China Hospital, West China School of Medicine, Sichuan University",
    "Haiyuan College of Kunming Medical University"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "BiaoFeng Fan"
    },
    {
      "affs": [
        0
      ],
      "name": "Qing Lei"
    },
    {
      "affs": [
        1
      ],
      "name": "HaoNan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "ChenJun Xin"
    },
    {
      "affs": [
        0
      ],
      "name": "XuanCheng Li"
    },
    {
      "affs": [
        0
      ],
      "name": "XiRui Zhu"
    },
    {
      "affs": [
        2
      ],
      "name": "JinXiang Kong"
    },
    {
      "affs": [
        0
      ],
      "name": "SiQi Xie"
    },
    {
      "affs": [
        0
      ],
      "name": "JianLiang Shang"
    },
    {
      "affs": [
        0
      ],
      "name": "ZuYang Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Chao Deng"
    },
    {
      "affs": [
        0
      ],
      "name": "DongJin Lv"
    },
    {
      "affs": [
        0
      ],
      "name": "WeiWei Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/515gwgvtn4g9x.bib",
  "cited_by": 0,
  "doi": "10.3389/fonc.2026.1960448",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13735745/",
  "id": "515gwgvtn4g9x",
  "issns": [
    "2234-943X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1960448/full",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ]
  ],
  "openalex": "W7223169361",
  "pdf_url": null,
  "pmcid": "PMC13735745",
  "pmid": "42991359",
  "published": "2026-10-22",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/515gwgvtn4g9x.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:13Z",
      "native_id": "10.3389/fonc.2026.1960448",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1960448/full"
    },
    {
      "first_seen": "2026-11-09T12:21:22Z",
      "native_id": "PMC13735745",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fonc.2026.1960448"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2234-943X",
      "subfield": "oncology"
    }
  ],
  "title": "SUMOylation counteracts ubiquitination to stabilize ANKRD1 and promote osimertinib resistance in lung adenocarcinoma",
  "title_text": "SUMOylation counteracts ubiquitination to stabilize ANKRD1 and promote osimertinib resistance in lung adenocarcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:21:22Z",
  "url": "https://research.draconitic.com/paper/515gwgvtn4g9x",
  "venue": "Frontiers in Oncology",
  "versions": []
}