Abstract LBA020: Targeting FGFR2c isoform, a novel therapeutic target with FGFR inhibitor in endometrial cancer
Authors: Sengal Asmerom T , Bonazzi Vanessa , Kondrashova Olga , Perrin Lewis , Chetty Naven , Smith Deborah , Gil-Moreno Antonio , Colas Eva , Pollock Pamela M 
Published: December 2021

Purpose: Endometrial cancer (EC) is the most frequently diagnosed gynaecological cancer. The majority of women with EC are treated surgically and have a good outcome, however 25-30% of patients presenting with metastases or recurrent disease do not have effective therapies and have &lt;12 months survival. Recent investigations demonstrated radio-chemotherapy has little benefit for women with high-risk EC within the deficient mismatch repair (dMMR) and p53 wild type (p53wt) molecular subtypes. We reported isoform switching from the FGFR2b (epithelial) splice-isoform to the FGFR2c (mesenchymal) splice-isoform in 40% of dMMR and 30% of p53wt ECs. This isoform switching was associated with adverse clinicopathologic markers, shorter recurrence free survival and disease specific survival in the Canadian cohort used to identify and validate the ProMisE molecular risk stratification approach. The objectives of the current study were i) to identify patient derived xenograft (PDX) models with FGFR2c expression and develop PDX derived organoids (PDXOs) for preclinical drug testing, ii) assess the efficacy of the BGJ398 FGFR inhibitor (FGFRi) in FGFR2c expressing models and generate preclinical data that would support an early phase clinical trial in FGFR2c stratified EC patients. Method: BaseScope RNA ISH was used to detect FGFR2c expression in patient tumours, PDX models and PDXOs. PDXOs derived from three independent PDX tumours were established from each of five PDX models (3 showing high FGFR2c expression, 2 showing low/no FGFR2c expression). Each PDXO culture was treated with 300nM BGJ398 (pan-FGFRi) or DMSO for 72 h and assessed using a live-dead assay and confocal microscopy. PDXs from three models were engrafted subcutaneously into 8 weeks female NSG mice and when tumours reached 100-150mm3, mice were randomized (4 mice/arm) and treated with 30mg/Kg BGJ398 or vehicle daily for 21 days. Tumours were measured 3x/week and mice sacrificed when tumours reached 900mm3. Results and conclusion: FGFR2c expression was higher in PDXs representing the dMMR and p53wt subtype compared to p53mut subtype and similar expression levels were seen between patient tumours, PDXs and PDXOs. In vitro FGFRi with BGJ398 showed significant cell death occurred in PDXOs with high FGFR2c expression (p&lt; 0.0001, 2-way ANOVA). These in vitro findings were validated in vivo using PDX68 carrying a FGFR2 C383R mutation and PDX52 and PDX59, both showing FGFR2 isoform switching. Significant tumour growth inhibition and a ~2-fold increase in survival was seen in all three models (PDX68, p&lt;0.0001 and p&lt;0.007; PDX52, p&lt;0.02 and P&lt;0.03; and PDX59 P&lt;0.0001 and P&lt;0.0006 respectively). In conclusion, our investigation revealed FGFRi (BGJ398) was effective in EC PDX models representing both mutational activation and isoform switching of FGFR2. As FGFR isoform switching occurs most commonly in the dMMR subtype where immune checkpoint inhibitors (ICIs) are approved, we propose the combination of ICIs and FGFRi may be more effective in women with FGFR2 activation compared to ICIs alone.

Citation Format: Asmerom T Sengal, Vanessa Bonazzi, Olga Kondrashova, Lewis Perrin, Naven Chetty, Deborah Smith, Antonio Gil-Moreno, Eva Colas, Pamela M Pollock. Targeting FGFR2c isoform, a novel therapeutic target with FGFR inhibitor in endometrial cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA020.