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PreprintCC BY-NC-NDbioRxiv

Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer

  • R. Y. Ebright
  • Y. He
  • A. G. Zhang
  • I. C. McCabe
  • C. U. Joisa
  • T. Thakar
  • J. Jen
  • D. T. Frederick
  • A. Acosta
  • G. Li
  • E. Kuehner
  • V. Yang
12 more authors
  • K. E. Doherty
  • N. Yaregal
  • N. N. K. Van
  • S. A. Zarmer
  • C. Luan
  • A. Dingley
  • E. Elwakeel
  • Y.-Y. Tseng
  • A. J. Aguirre
  • J. M. Cleary
  • J. J. Yeh
  • W. R. Sellers1
  1. 1Broad Institute
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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.

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Cite

BibTeXRIS
BibTeX
@misc{ebright2026contextspecific,
  title = {{Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer}},
  author = {R. Y. Ebright and Y. He and A. G. Zhang and I. C. McCabe and C. U. Joisa and T. Thakar and J. Jen and D. T. Frederick and A. Acosta and G. Li and E. Kuehner and V. Yang and K. E. Doherty and N. Yaregal and N. N. K. Van and S. A. Zarmer and C. Luan and A. Dingley and E. Elwakeel and Y.-Y. Tseng and A. J. Aguirre and J. M. Cleary and J. J. Yeh and W. R. Sellers},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.24.754062},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer
AU  - R. Y. Ebright
AU  - Y. He
AU  - A. G. Zhang
AU  - I. C. McCabe
AU  - C. U. Joisa
AU  - T. Thakar
AU  - J. Jen
AU  - D. T. Frederick
AU  - A. Acosta
AU  - G. Li
AU  - E. Kuehner
AU  - V. Yang
AU  - K. E. Doherty
AU  - N. Yaregal
AU  - N. N. K. Van
AU  - S. A. Zarmer
AU  - C. Luan
AU  - A. Dingley
AU  - E. Elwakeel
AU  - Y.-Y. Tseng
AU  - A. J. Aguirre
AU  - J. M. Cleary
AU  - J. J. Yeh
AU  - W. R. Sellers
PY  - 2026
DA  - 2026/09/24
PB  - bioRxiv
DO  - 10.64898/2026.09.24.754062
UR  - https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1
AB  - 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.
ER  -