{
  "abstract": "Resistance of lung cancer to EGFR-targeting tyrosine kinase inhibitors (TKIs) like osimertinib frequently results from secondary mutations or activation of bypass signaling pathways. Re-analysis of clinical data unveiled elevated expression of GAS6 and its receptor MERTK in lung cancer patients developing resistance to osimertinib. This implied that the GAS6-MERTK axis could represent a therapeutic vulnerability. Functionally, GAS6 overexpression enhanced cancer cell survival, whereas a new anti-GAS6 antibody delayed tumor relapses in xenograft models. Similarly, ablation of MERTK sensitized lung cancer cells to osimertinib, revealing a bypass crosstalk between EGFR and MERTK, likely taking place within caveolae. An anti-MERTK antibody was generated, and a bispecific antibody, Bis-EM, targeting both EGFR and MERTK, was designed. Bis-EM promoted the degradation of both receptors and displayed the capacity to promote immune-mediated cell killing. In combination with TKIs, concurrent antibody-mediated inhibition of MERTK and EGFR suppressed the growth of TKI-resistant spheroids. Co-treatment with Bis-EM and TKIs delayed tumor relapses in an Fc-dependent manner across patient-derived xenografts harboring clinically challenging EGFR exon 20 insertions and other mutations. Collectively, these findings identify the GAS6-MERTK axis as an important driver of drug resistance and provide a strong rationale for the clinical development of Bis-EM.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.",
    "Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.",
    "Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.",
    "Department of System Immunology, Weizmann Institute of Science, Rehovot, Israel.",
    "Graduate School of Pharmaceutical Sciences, The University of Osaka, Osaka, Japan.",
    "Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK.",
    "Division of Bimolecular Science and Medicinal Chemistry, School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham, UK.",
    "Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK.",
    "Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.",
    "Graduate School of Medicine, The University of Osaka, Osaka, Japan.",
    "Institute for Open and Transdisciplinary Research Initiatives, The University of Osaka, Osaka, Japan.",
    "Global Center for Medical Engineering and Informatics, The University of Osaka, Osaka, Japan.",
    "R3 Institute for Newly-Emerging Science Design, The University of Osaka, Osaka, Japan.",
    "Department of Life Science Core Facility, Weizmann Institute of Science, Rehovot, Israel.",
    "The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.",
    "Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.",
    "IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 29,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Suvendu Giri",
      "orcid": "0000-0002-7595-1359"
    },
    {
      "affs": [
        0
      ],
      "name": "Boobash Raj Selvadurai",
      "orcid": "0000-0002-8132-583X"
    },
    {
      "affs": [
        0
      ],
      "name": "Nitin Gupta",
      "orcid": "0000-0001-6485-6113"
    },
    {
      "affs": [
        0
      ],
      "name": "Arturo Simoni-Nieves",
      "orcid": "0000-0002-1353-260X"
    },
    {
      "affs": [
        0
      ],
      "name": "Alessandro Genna",
      "orcid": "0000-0003-4821-1491"
    },
    {
      "affs": [
        0
      ],
      "name": "Moshit Lindzen"
    },
    {
      "affs": [
        0
      ],
      "name": "Rishita Chatterjee",
      "orcid": "0000-0001-8484-3897"
    },
    {
      "affs": [
        0
      ],
      "name": "Marieke Van Daele",
      "orcid": "0000-0002-3832-0662"
    },
    {
      "affs": [
        0
      ],
      "name": "Deepthi Ramesh Kumar",
      "orcid": "0000-0002-8987-2213"
    },
    {
      "affs": [
        1
      ],
      "name": "Mirie Zerbib"
    },
    {
      "affs": [
        1
      ],
      "name": "Roni Oren",
      "orcid": "0000-0003-1228-412X"
    },
    {
      "affs": [
        0
      ],
      "name": "Isabelle Sophie Meijer"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Elisabeth Franziska Wippich",
      "orcid": "0009-0007-9825-8358"
    },
    {
      "affs": [
        3
      ],
      "name": "Yahel Avraham",
      "orcid": "0000-0002-6068-4892"
    },
    {
      "affs": [
        3
      ],
      "name": "Rony Dahan",
      "orcid": "0000-0002-8420-7601"
    },
    {
      "affs": [
        4
      ],
      "name": "Yuya Haga",
      "orcid": "0000-0003-4148-2256"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Laura E Kilpatrick",
      "orcid": "0000-0001-6331-5606"
    },
    {
      "affs": [
        5,
        7
      ],
      "name": "Simon Platt",
      "orcid": "0000-0002-8418-3646"
    },
    {
      "affs": [
        5,
        7
      ],
      "name": "Stephen J Hill",
      "orcid": "0000-0002-4424-239X"
    },
    {
      "affs": [
        8
      ],
      "name": "Lipika R Pal",
      "orcid": "0000-0002-3390-110X"
    },
    {
      "affs": [
        8
      ],
      "name": "Eytan Ruppin"
    },
    {
      "affs": [
        4,
        9,
        10,
        11,
        12
      ],
      "name": "Yasuo Tsutsumi"
    },
    {
      "affs": [
        13
      ],
      "name": "Eliane Hadas Yardeni",
      "orcid": "0009-0007-3898-5035"
    },
    {
      "affs": [
        14
      ],
      "name": "Muhammad Abu Ahmad",
      "orcid": "0009-0001-6613-2044"
    },
    {
      "affs": [
        14
      ],
      "name": "Olga Radinsky"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Donatella Romaniello",
      "orcid": "0000-0001-8278-1637"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Mattia Lauriola",
      "orcid": "0000-0002-7966-0065"
    },
    {
      "affs": [
        14
      ],
      "name": "Angel Porgador",
      "orcid": "0000-0003-1540-4449"
    },
    {
      "affs": [
        0
      ],
      "name": "Yosef Yarden",
      "orcid": "0000-0001-8578-0250"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3j326nqhdq4gq.bib",
  "cited_by": 0,
  "doi": "10.1002/advs.78290",
  "fulltext_url": "https://europepmc.org/articles/PMC13669479",
  "id": "3j326nqhdq4gq",
  "issns": [
    "2198-3844"
  ],
  "landing_url": "https://europepmc.org/article/MED/42875888",
  "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": [
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ]
  ],
  "openalex": "W7222267468",
  "pdf_url": "https://europepmc.org/articles/PMC13669479?pdf=render",
  "pmcid": "PMC13669479",
  "pmid": "42875888",
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3j326nqhdq4gq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:46Z",
      "native_id": "MED:42875888",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42875888"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Lung Cancer Treatments and Mutations",
      "subfield": "general"
    }
  ],
  "title": "Fc-Dependent Targeting of the GAS6-MERTK Axis With Monoclonal and Bispecific Antibodies Overcomes Drug Resistance Across EGFR Mutations in Exons 19, 20, and 21.",
  "title_text": "Fc-Dependent Targeting of the GAS6-MERTK Axis With Monoclonal and Bispecific Antibodies Overcomes Drug Resistance Across EGFR Mutations in Exons 19, 20, and 21.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:46Z",
  "url": "https://research.draconitic.com/paper/3j326nqhdq4gq",
  "venue": "Advanced science (Weinheim, Baden-Wurttemberg, Germany)",
  "versions": []
}