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

Ebright, R. Y.; He, Y.; Zhang, A. G.; McCabe, I. C.; Joisa, C. U.; Thakar, T.; Jen, J.; Frederick, D. T.; Acosta, A.; Li, G.; Kuehner, E.; Yang, V.; Doherty, K. E.; Yaregal, N.; Van, N. N. K.; Zarmer, S. A.; Luan, C.; Dingley, A.; Elwakeel, E.; Tseng, Y.-Y.; Aguirre, A. J.; Cleary, J. M.; Yeh, J. J.; Sellers, W. R.

doi:10.64898/2026.09.24.754062

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bioRxiv · 10.64898/2026.09.24.754062

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

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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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Ebright, R. Y., He, Y., Zhang, A. G., McCabe, I. C., Joisa, C. U., Thakar, T., Jen, J., Frederick, D. T., Acosta, A., Li, G., Kuehner, E., Yang, V., Doherty, K. E., Yaregal, N., Van, N. N. K., Zarmer, S. A., Luan, C., Dingley, A., Elwakeel, E., Tseng, Y.-Y., Aguirre, A. J., Cleary, J. M., Yeh, J. J., Sellers, W. R.. 2026-09-25. Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer. https://doi.org/10.64898/2026.09.24.754062

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