{
  "abstract": "Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting with KRAS G12D mutations. The recent development of small molecule inhibitors targeting KRAS G12D has enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRAS G12D inhibition and mechanism/s of resistance to KRAS G12D suppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRAS G12D inhibition with MRTX1133. While KRAS G12D inhibition initially increases CD11c + cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRAS G12D therapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS G12D inhibition with prolonged survival with translational implications.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Bioengineering, Rice University, Houston, TX, USA. rkalluri@mdanderson.org",
    "Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA. rkalluri@mdanderson.org",
    "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. rkalluri@mdanderson.org",
    "Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. rkalluri@mdanderson.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 32,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kathleen M. McAndrews",
      "orcid": "0000-0002-4092-4991"
    },
    {
      "affs": [
        0
      ],
      "name": "Krishnan K. Mahadevan",
      "orcid": "0000-0002-6503-6851"
    },
    {
      "affs": [
        0
      ],
      "name": "Bingrui Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Anaïs M Comptdaer"
    },
    {
      "affs": [
        0
      ],
      "name": "Amari M. Sockwell",
      "orcid": "0009-0008-1963-4181"
    },
    {
      "affs": [
        0
      ],
      "name": "Sami J. Morse",
      "orcid": "0009-0001-2796-2010"
    },
    {
      "affs": [
        0
      ],
      "name": "Patience J. Kelly"
    },
    {
      "affs": [
        0
      ],
      "name": "Sarah I. Patel"
    },
    {
      "affs": [
        0
      ],
      "name": "Michelle L. Kirtley",
      "orcid": "0009-0009-1960-3032"
    },
    {
      "affs": [
        0
      ],
      "name": "Barbara A. Moreno Diaz"
    },
    {
      "affs": [
        1
      ],
      "name": "Hengyu Lyu",
      "orcid": "0000-0003-1093-9364"
    },
    {
      "affs": [
        1
      ],
      "name": "David H. Peng",
      "orcid": "0000-0003-0511-1888"
    },
    {
      "affs": [
        1
      ],
      "name": "Sima Khazaei",
      "orcid": "0000-0002-0929-9366"
    },
    {
      "affs": [
        1
      ],
      "name": "Aislyn P. Schalck",
      "orcid": "0000-0002-4020-1822"
    },
    {
      "affs": [
        0
      ],
      "name": "Xunian Zhou",
      "orcid": "0000-0002-3287-8913"
    },
    {
      "affs": [
        0
      ],
      "name": "Hikaru Sugimoto",
      "orcid": "0000-0003-0499-3962"
    },
    {
      "affs": [
        0
      ],
      "name": "Aaron A. Bickert"
    },
    {
      "affs": [
        0
      ],
      "name": "Lakshmi Kavitha Sthanam",
      "orcid": "0000-0002-8430-3505"
    },
    {
      "affs": [
        0
      ],
      "name": "M P H Sarah Taylor"
    },
    {
      "affs": [
        0
      ],
      "name": "Shreyasee V. Kumbhar"
    },
    {
      "affs": [
        0
      ],
      "name": "Kent A. Arian"
    },
    {
      "affs": [
        0
      ],
      "name": "Yasaman Barekatain",
      "orcid": "0000-0002-4454-1496"
    },
    {
      "affs": [
        2
      ],
      "name": "Francesca Paradiso",
      "orcid": "0000-0001-6926-1119"
    },
    {
      "affs": [
        2
      ],
      "name": "Paola A. Guerrero",
      "orcid": "0000-0002-7345-1246"
    },
    {
      "affs": [
        3
      ],
      "name": "Vincent Bernard",
      "orcid": "0000-0003-1555-608X"
    },
    {
      "affs": [
        0
      ],
      "name": "Navid Sobhani",
      "orcid": "0000-0003-1381-0283"
    },
    {
      "affs": [
        0
      ],
      "name": "Alondra N Camacho-Acevedo"
    },
    {
      "affs": [
        0
      ],
      "name": "Kiara E. Bornes",
      "orcid": "0000-0002-8394-8977"
    },
    {
      "affs": [
        0
      ],
      "name": "Phương Thảo Trần",
      "orcid": "0009-0005-5207-1403"
    },
    {
      "affs": [
        4,
        2
      ],
      "name": "Anirban Maitra",
      "orcid": "0000-0001-7923-9978"
    },
    {
      "affs": [
        1
      ],
      "name": "Timothy Paul Heffernan",
      "orcid": "0000-0002-3166-8922"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Raghu Kalluri",
      "orcid": "0000-0002-2190-547X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8dv3w3z49spwa.bib",
  "cited_by": 10,
  "doi": "10.1038/s44318-026-00854-5",
  "fulltext_url": null,
  "id": "8dv3w3z49spwa",
  "issns": [
    "0261-4189",
    "1460-2075"
  ],
  "landing_url": "https://doi.org/10.1038/s44318-026-00854-5",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Pancreatic and Hepatic Oncology Research"
    ]
  ],
  "openalex": "W7168048069",
  "pdf_url": null,
  "pmcid": "PMC12338590",
  "pmid": "40791564",
  "published": "2026-07-11",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/8dv3w3z49spwa.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:15Z",
      "native_id": "W7168048069",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s44318-026-00854-5"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research",
      "subfield": "oncology"
    }
  ],
  "title": "CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC",
  "title_text": "CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T13:21:08Z",
  "url": "https://research.draconitic.com/paper/8dv3w3z49spwa",
  "venue": "The EMBO Journal",
  "versions": []
}