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

  1. Richard Y. Ebright
  2. Yao He
  3. Alan G. Zhang
  4. Ian C. McCabe
  5. Chinmaya U. Joisa
  6. Tanay Thakar
  7. Jayu Jen
  8. Dennie T. Frederick
  9. Arianny Acosta
  10. Guangyan Li
  11. Elena Kuehner
  12. Vivian Yang
  13. Katherine E. Doherty
  14. Natnael Yaregal
  15. Ngan N. K. Van
  16. Sandra A. Zarmer
  17. Changfei Luan
  18. Aurelia Dingley
  19. Eiman Elwakeel
  20. Yuen-Yi Tseng
  21. Andrew J. Aguirre
  22. James M. Cleary
  23. Jen Jen Yeh
  24. William R. Sellers
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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 KRAS mut 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.

STATEMENT OF SIGNIFICANCE

The recent approval of daraxonrasib makes RAS inhibition standard-of-care in pancreatic cancer, but resistance inevitably develops. Unbiased digenic CRISPR screening identified FGFR signaling as a prominent resistance axis potently activated by stromal FGF ligands. The addition of an approved FGFR inhibitor to RAS inhibition eradicates tumor cells and prolongs response, offering an immediately actionable combination.

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  1. Mentioned by @uncited.org on Bluesky

    Ebright et al. in the Sellers Lab at Broad Institute map genetic interactions in pancreatic cancer, revealing that combined KRAS and FGFR inhibition is synergistic and cytotoxic, overcoming resistance and enhancing treatment efficacy.

  2. Mentioned by @prepub-singlecell.bsky.social on Bluesky

    Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer #SingleCell 🧪🧬🖥️ https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1

  3. Mentioned by @biorxiv-cancer.bsky.social on Bluesky

    Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1

  4. Mentioned by @biorxivpreprint.bsky.social on Bluesky

    Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer https://www.biorxiv.org/content/10.64898/2026.09.24.754062v1

  5. Version published to 10.64898/2026.09.24.754062v1 on bioRxiv