Abstract 4575: FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability

Abstract

Abstract Fibroblast Growth Factor 3 (FGFR3) genomic alterations are oncogenic drivers in ~15% of bladder cancer patients. A novel FGFR inhibitor, Erdafitinib, was FDA approved in 2019 based off a Phase II trial with an overall response rate of 40%. However, the majority of patients rapidly relapse at a median of 6 months, requiring combination therapies to prevent drug resistance. We hypothesized that a genome-wide CRISPR screen would identify Erdafitinib-sensitizing co-targets. We screened UM-UC-14, an S249C FGFR3 mutated bladder cancer cell line, and identified Cyclin C as a top hit in addition to known MAPK effectors such as ERK2 and SHP2. Cyclin C is a non-cell cycle related cyclin and part of the CDK8/19 kinase module of Mediator. Pharmacological validation in 4 FGFR3 altered cell lines confirmed a high degree of synergy between Erdafitinib and the CDK8/19 inhibitor Sel120, while no effect was seen in 2 wildtype cell lines, suggesting strong specificity. Moreover, the synergy in FGFR3-mutant cells was superior to that of SHP2 inhibitor SHP099 or the ERK inhibitor BVD-523. Similarly, GATA3 and PPARG also scored highly in our CRISPR screen. These transcription factors have been shown to be sufficient to enforce a luminal identity but not necessarily to maintain it. We validated these 3 genes as sensitizers and show in luminal cells that loss of either GATA3 or PPARG leads to loss of luminal markers and gain of basal markers. In contrast, cells treated with Sel120 showed, on RNAseq, an increase in basal markers without loss of luminal markers. Interestingly, our data suggests that the gain of basal markers, commonly associated with a worse prognosis, is associated with a strong sensitization to FGFR inhibition in FGFR3 alteration driven bladder cancer. We conducted a xenograft experiment confirming that mice responded well to single agent Erdafitinib, but without frank tumor regression. By contrast, Sel120+Erdafitinib induced complete responses in 8/10 mice compared to 6/10 mice for SHP099+Erdafitinib. Remarkably, after 60 days of daily drugging and a 20-day washout, the tumors did not grow back in the complete responders. Importantly, no loss of body weight or other signs of morbidity were found. Our results suggest an immediate and promising benefit in combining either CDK8/19 or SHP2 inhibitors with Erdafitinib in treating patients with FGFR3 alteration driven bladder cancers. Furthermore, we identified a strategy in targeting lineage modulators as sensitizers to existing therapies. Citation Format: Mohamad Karim Koleilat, Yan Zhu, Lawrence Kwong. FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4575.