Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer

ABSTRACT Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed 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 investigated 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 produced 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 reversed these changes and synergized 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. Competing Interest Statement J.J.Z. is a co-founder and director of Crimson BioPharma Inc. and Geode Therapeutics Inc. (not related to this work). G.J.F. has patents and pending royalties related to the PD-L1/PD-1 pathway from Roche, Merck MSD, AstraZeneca, Bristol-Myers Squibb, Merck KGaA, 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 (not related to this work). G.I.S. receives research funding from Merck KGaA/EMD Serono, Artios, Eli Lilly, and Pfizer. He has served on advisory boards for Merck KGaA/EMD Serono, Circle Pharmaceuticals, Concarlo Therapeutics, Schrodinger, FoRx Therapeutics, and MycRx. He holds patents entitled "Dosage regimen for sapacitabine and seliciclib" and "Compositions and Methods for Predicting Response and Resistance to CDK4/6 inhibition" (not related to this work).