{
  "abstract": "Targeted therapies directed against oncogenic signaling addictions, such as inhibitors of ALK in ALK+ NSCLC often induce strong and durable clinical responses. However, they are not curative in metastatic cancers, as some tumor cells persist through therapy, eventually developing resistance. Therapy sensitivity can reflect not only cell-intrinsic mechanisms but also inputs from stromal microenvironment. Yet, the contribution of tumor stroma to therapeutic responses in vivo remains poorly defined. To address this gap of knowledge, we assessed the contribution of stroma-mediated resistance to therapeutic responses to the frontline ALK inhibitor alectinib in xenograft models of ALK+ NSCLC. We found that stroma-proximal tumor cells are partially protected against cytostatic effects of alectinib. This effect is observed not only in remission, but also during relapse, indicating the strong contribution of stroma-mediated resistance to both persistence and resistance. This therapy-protective effect of the stromal niche reflects a combined action of multiple mechanisms, including growth factors and extracellular matrix components. Consequently, despite improving alectinib responses, suppression of any individual resistance mechanism was insufficient to fully overcome the protective effect of stroma. Focusing on shared collateral sensitivity of persisters offered a superior therapeutic benefit, especially when using an antibody-drug conjugate with bystander effect to limit therapeutic escape. These findings indicate that stroma-mediated resistance might be the major contributor to both residual and progressing disease and highlight the limitation of focusing on suppressing a single resistance mechanism at a time.",
  "abstract_shown": true,
  "affiliations": [
    "Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA",
    "Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA",
    "Department of Integrated Mathematical Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA",
    "Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA",
    "Department of Machine Learning, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA",
    "Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA",
    "Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA",
    "Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany",
    "Department of Thoracic Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA",
    "Department of Molecular Medicine, University of South Florida, Tampa, FL, USA. andriy.marusyk@moffitt.org",
    "Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. andriy.marusyk@moffitt.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Bina Desai",
      "orcid": "0000-0003-0454-7583"
    },
    {
      "affs": [
        2
      ],
      "name": "Tatiana Miti",
      "orcid": "0000-0001-6842-8036"
    },
    {
      "affs": [
        2
      ],
      "name": "Sandhya Prabhakaran",
      "orcid": "0000-0002-9537-507X"
    },
    {
      "affs": [
        1
      ],
      "name": "Daria Miroshnychenko",
      "orcid": "0000-0001-6425-5000"
    },
    {
      "affs": [
        1
      ],
      "name": "Pragya Kumar",
      "orcid": "0009-0007-7360-1631"
    },
    {
      "affs": [
        1
      ],
      "name": "Menkara Henry"
    },
    {
      "affs": [
        1
      ],
      "name": "Viktoriya Marusyk",
      "orcid": "0009-0004-5736-1365"
    },
    {
      "affs": [
        1
      ],
      "name": "Natália Souza Nunes Siqueira",
      "orcid": "0000-0002-7877-2655"
    },
    {
      "affs": [
        2
      ],
      "name": "Chandler Gatenbee",
      "orcid": "0000-0002-9730-5964"
    },
    {
      "affs": [
        3
      ],
      "name": "Hilal Özakıncı",
      "orcid": "0000-0001-7921-1000"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Marilyn Bui",
      "orcid": "0000-0003-4963-2255"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Theresa A. Boyle",
      "orcid": "0000-0001-5950-3970"
    },
    {
      "affs": [
        6
      ],
      "name": "Jacob Scott",
      "orcid": "0000-0003-2971-7673"
    },
    {
      "affs": [
        7
      ],
      "name": "Philipp M. Altrock",
      "orcid": "0000-0001-7731-3345"
    },
    {
      "affs": [
        3,
        8
      ],
      "name": "Bruna Pellini",
      "orcid": "0000-0003-0898-0202"
    },
    {
      "affs": [
        3
      ],
      "name": "Eric B. Haura",
      "orcid": "0000-0003-3114-1909"
    },
    {
      "affs": [
        2
      ],
      "name": "Alexander R.A. Anderson",
      "orcid": "0000-0002-2536-4383"
    },
    {
      "affs": [
        2
      ],
      "name": "David Basanta",
      "orcid": "0000-0002-8527-0776"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Andriy Marusyk",
      "orcid": "0000-0002-0087-9575"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9eavp2410w1yt.bib",
  "cited_by": 10,
  "doi": "10.1038/s41467-026-73454-w",
  "fulltext_url": null,
  "id": "9eavp2410w1yt",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-73454-w",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ]
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  "openalex": "W7162777515",
  "pdf_url": null,
  "pmcid": "PMC11071426",
  "pmid": "38712093",
  "published": "2026-05-29",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/9eavp2410w1yt.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:15Z",
      "native_id": "W7162777515",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41467-026-73454-w"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Lung Cancer Treatments and Mutations",
      "subfield": "general"
    }
  ],
  "title": "Multifactorial sheltering in peristromal niches shapes in vivo responses of lung cancers to targeted therapies",
  "title_text": "Multifactorial sheltering in peristromal niches shapes in vivo responses of lung cancers to targeted therapies",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:39Z",
  "url": "https://research.draconitic.com/paper/9eavp2410w1yt",
  "venue": "Nature Communications",
  "versions": []
}