Poster Presentation 38th Lorne Cancer Conference 2026

FGFR2 spatial isoforms in tumour progression and prognosis, and emerging novel target in endometrial cancer precision therapy (#252)

Asmerom T Sengal 1 2 , Rohan Lourie 3 , Naven Chetty 4 , Pamela Pollock 5 , Kum Kum Khanna 1
  1. Mater Research Institute (MRI), Mater Research Institute (MRI)-University of Queensland, Translational Research Institute (TRI), Brisbane, QLD, Australia
  2. Mater Research Institute (MRI)-University of Queensland, Mater Research Institute (MRI)-University of Queensland, translational Research Institute (TRI), Brisbane, QLD, Australia
  3. Mater Pathology, Mater Hospital and UQ, Brisbane, QLD, Australia
  4. Gynaecological Oncology, Mater Health Service , Brisbane, QLD, Australia
  5. Endometrial Cancer Laboratory, School of Biomedical Sciences, Faculty Of Health, Queensland University of Technology @Translational Research Institute, Brisbane, QLD, Australia

Endometrial cancer (EC) is the most frequently diagnosed gynaecological cancer in developed countries, including Australia, and its incidence is projected to increase by 150% by 2040 in Australia. Women with metastatic and/or recurrent EC have limited treatment options and poor survival outcomes, with a median 5-year survival rate of 15%.

Fibroblast Growth Factor Receptor 2 (FGFR2) has two main splice isoforms, FGFR2b (epithelial) and FGFR2c(mesenchymal), that are differentially expressed in epithelial and mesenchymal cells, respectively, in normal tissue.  

We developed and validated a novel technique to detect FGFR2 splice isoforms at single-cell resolution using BaseScope RNA in situ hybridisation. We reported isoform switching from the FGFR2b splice-isoform to the oncogenic FGFR2c splice-isoform in 30-40% ECs. High FGFR2c was associated with shorter recurrence-free survival and disease-specific survival in two cohorts of patients (n=450) [1-2]. We developed EC preclinical models (patient-derived xenografts (PDXs) and organoids with high FGFR2c (oncogenic isoform) expression.  In vitro targeting of 4 independent EC organoids with high FGFR2c expression with clinically available FGFR inhibitor (300nM BGJ398) showed significant cell death in the treated arm compared to the control or FGFR2c negative models. We have validated this funding with shRNA-mediated FGFR2 knockdown, and a similar impact was noted [3]. Functional in vitro experiments also revealed knockdown of FGFC2c resulted in organoid growth inhibition, mesenchymal- epithelial transition (MET) and decreased cell stemness. Furthermore, the in vitro results were validated using in vivo by targeting high FGFR2c expression EC PDX models (with 5mg/Kg BGJ398 daily for 21 days) and results showed significant tumour growth inhibition and longer survival compared to the vehicle-treated arms. In vivo study also showed that FGFR2c promotes tumour proliferation, angiogenesis, M2 macrophage polarisation. In conclusion, FGFR2c oncogenic splice isoform enhances EC tumour growth and progression through autocrine signalling, and it is a novel prognostic, predictive and therapeutic target in EC.

  1. 1. Sengal, A.T. et al. FGFR2c Mesenchymal Isoform Expression Is Associated with Poor Prognosis and Further Refines Risk Stratification within Endometrial Cancer Molecular Subtypes. Clinical Cancer Research 26, 4569-4580 (2020). 2. Sengal A, Smith, D, Snell CE,. Spatial Expression of FGFR2b Splice Isoform and its Prognostic Significance in Endometrioid Endometrial Carcinoma. J Pathol Clin Res. 2022;8(6):521-37. 3. Sengal AT, Bonazzi V, Smith D, Moiola CP, Lourie R, Rogers R, et al. Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition. npj Precision Oncology. 2023;7(1):127.