Abstract
Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we develop a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic PIK3CA mutation, Trp53 loss, and MYC overexpression. Using this model together with human EC cell lines, patient-derived organoids (PDOs), xenografts, and patient datasets, we investigate mechanisms underlying resistance to PI3Kα-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3Kα inhibition produces superior tumor control compared with either agent alone. Mechanistically, FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen presentation and enriching M2-type tumor-associated macrophages. FGFR inhibition reverses these changes and synergizes with anti-PD-1 therapy to enhance antitumor immune responses and establish durable immune memory. Collectively, these findings identify FGFR signaling as a key driver of therapeutic resistance and immune escape in SEC and support FGFR-targeted combination strategies.
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Acknowledgements
We thank Drs. J.A. Sanai, G.B. Mills, and D. Chowdhury for kindly providing EC cell lines. We also thank the Center for Cancer Genomics team for their assistance with snRNA sequencing. This work was supported by grants from the National Cancer Institute (NCI) under award number 1P01CA269021-01A1 (G.I.S., J.L., P.K., U.M., and J.J.Z.) and from the National Institutes of Health (NIH) under award numbers R35CA210057 (J.J.Z.), 1P01CA236749 (G.J.F.), and AI056299 (G.J.F.). K.C. was supported by a start-up fund provided by Boston Children’s Hospital. This work was also supported in part by the Expect Miracles Foundation and the Robert A. and Renée E. Belfer Family Foundation.
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G.J.F. has patents/pending royalties related to the PD-L1/PD-1 pathway from Roche, Merck MSD, AstraZeneca, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, Dako, Leica, Mayo Clinic, Eli Lilly, and Novartis. G.J.F. has served on advisory boards for iTeos, NextPoint, IgM, GV20, IOME, Bioentre, Santa Ana Bio, Simcere of America, and Geode and holds equity in Nextpoint, iTeos, IgM, Invaria, GV20, Bioentre, and Geode. G.I.S. receives research funding from Merck KGaA/EMD Serono, Artios, Eli Lilly, and Pfizer and has served on advisory boards for Merck KGaA/EMD Serono, Circle Pharmaceuticals, Concarlo Therapeutics, Schrodinger, FoRx Therapeutics, and MycRx. G.I.S. holds patents entitled “Dosage regimen for sapacitabine and seliciclib” and “Compositions and Methods for Predicting Response and Resistance to CDK4/6 inhibition”. J.J.Z. is a co-founder and director of Crimson BioPharma Inc. and Geode Therapeutics Inc. All these activities are not related to this work. The remaining authors declare no competing interests.
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Cheng, X., Zhang, Y., Qian, C. et al. Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72544-z
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DOI: https://doi.org/10.1038/s41467-026-72544-z
