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<p>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 <i>PIK3CA</i> mutation, <i>Trp53</i> loss, and <i>MYC</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Xin Cheng,
  • Yadong Zhang,
  • Changli Qian,
  • Erica Holdridge,
  • Guruprasad Ananda,
  • Tao Jiang,
  • Jing Ni,
  • Shaozhen Xie,
  • Hao Gu,
  • Renlei Ji,
  • Elena V. Ivanova,
  • Marisa R. Nucci,
  • Zhe Wang,
  • Kaifu Chen,
  • Bose Kochupurakkal,
  • Gordon J. Freeman,
  • Geoffrey I. Shapiro,
  • Joyce Liu,
  • Panagiotis A. Konstantinopoulos,
  • Ursula Matulonis,
  • Jean J. Zhao

摘要

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.