Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer
Cheng, X.; Qian, C.; Holdridge, E.; Ananda, G.; Jiang, T.; Zhang, Y.; Ni, J.; Xie, S.; Gu, H.; Ji, R.; Ivanova, E. V.; Nucci, M. R.; Wang, Z.; Chen, K.; Kochupurakkal, B.; Freeman, G. J.; Shapiro, G. I.; Liu, J.; Konstantinopoulos, P. A.; Matulonis, U.; Zhao, J. J.
Show 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 PI3K-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3K 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors 98%
- Combinatorial immunotherapies overcome MYC-driven immune evasion 98%
- A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer 97%
Similar papers in this journal
- Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma 96%
- Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets 96%
- Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma 96%
Similar papers in this journal
- Cancer-associated fibroblast compositions change with breast cancer progression linking S100A4 and PDPN ratios with clinical outcome 97%
- Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance 97%
- Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma 96%
Similar papers in this journal
- Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells 97%
- Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy 96%
- G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program 96%
Similar papers in this journal
- Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer 97%
- Tumor-educated Gr1+CD11b+ cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6-JAK signaling 97%
- The MNK1/2-eIF4E axis contributes to phenotype switching, melanoma progression, and resistance to immunotherapy. 97%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.