{
  "abstract": "Oncogenic KRAS drives >90% of pancreatic ductal adenocarcinoma (PDAC), and the pan-RAS inhibitor daraxonrasib doubles overall survival, but adaptive and acquired resistance limit the depth and duration of responses. To systematically map combination vulnerabilities, we developed RAS+, a digenic CRISPR knockout library testing 10,296 pairwise perturbations across oncogenic signaling pathways, and screened 12 cell lines, revealing genotype- and lineage-specific interactions. In KRASmut PDAC, the most differentially effective gene pair was KRAS and FRS2, an adapter coupling FGFR signaling to RAS. Combined KRAS/pan-FGFR inhibition was synergistic and cytotoxic, eradicating tumor cells and overcoming resistance in vitro and deepening and prolonging regressions in vivo. Single-cell analysis identified cancer-associated fibroblasts (CAFs) as a primary source of FGF ligands in PDAC, and CAF conditioned media or individual FGFs promoted resistance. These findings define a stroma-to-tumor adaptive FGFR circuit limiting the effects of KRAS inhibition. Thus, combined KRAS/FGFR blockade may be a strategy to improve responses.",
  "abstract_shown": true,
  "affiliations": [
    "Broad Institute"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "name": "R. Y. Ebright"
    },
    {
      "name": "Y. He"
    },
    {
      "name": "A. G. Zhang"
    },
    {
      "name": "I. C. McCabe"
    },
    {
      "name": "C. U. Joisa"
    },
    {
      "name": "T. Thakar"
    },
    {
      "name": "J. Jen"
    },
    {
      "name": "D. T. Frederick"
    },
    {
      "name": "A. Acosta"
    },
    {
      "name": "G. Li"
    },
    {
      "name": "E. Kuehner"
    },
    {
      "name": "V. Yang"
    },
    {
      "name": "K. E. Doherty"
    },
    {
      "name": "N. Yaregal"
    },
    {
      "name": "N. N. K. Van"
    },
    {
      "name": "S. A. Zarmer"
    },
    {
      "name": "C. Luan"
    },
    {
      "name": "A. Dingley"
    },
    {
      "name": "E. Elwakeel"
    },
    {
      "name": "Y.-Y. Tseng"
    },
    {
      "name": "A. J. Aguirre"
    },
    {
      "name": "J. M. Cleary"
    },
    {
      "name": "J. J. Yeh"
    },
    {
      "affs": [
        0
      ],
      "name": "W. R. Sellers"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0petp3ebg3k0b.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.754062",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1.full",
  "id": "0petp3ebg3k0b",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2730|Pancreatic and Hepatic Oncology Research"
    ]
  ],
  "openalex": "W7214286392",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0petp3ebg3k0b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:32Z",
      "native_id": "10.64898/2026.09.24.754062",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer",
  "title_text": "Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:32Z",
  "url": "https://research.draconitic.com/paper/0petp3ebg3k0b",
  "venue": "bioRxiv",
  "versions": []
}