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Preprint WatchModerateSeptember 22nd, 2026

Distinct phenotypic consequences of cholangiocarcinoma-associated FGFR2 alterations depend on biliary epithelial cell state

Chiasson-MacKenzie, C., Zhang, Y., O'Loughlin, E., Dave, P., Menon, A. S., Vijay, V. et al.

Oncogenic FGFR2 fusions and in-frame deletions disrupt biliary lumen morphogenesis in distinct ways, and the trafficking, signaling and phenotypic output of each FGFR2 mutant is governed by the epithelial state of the host cell.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Chiasson-MacKenzie and colleagues (bioRxiv version 3, not peer reviewed) use a 3D biliary morphogenesis model to show that FGFR2 fusions and in-frame deletions each disrupt lumen formation differently, and that receptor trafficking and signaling depend on the epithelial state of the cell. Claidex holds two FGFR2 failures, both with the FGFR2b antibody bemarituzumab: the Phase 3 FORTITUDE-102 gastric program, whose effect estimate did not hold (bemarituzumab-fgfr2b-gastric-gej-fortitude-102-phase3-efficacy-termination), and the FGFR2b-overexpressing solid tumor basket cut after benefit concentrated in gastric cancer (bemarituzumab-fgfr2-fgfr2b-overexpressing-solid-tumors-phase1b2-strategic-termination). The preprint concerns genomic FGFR2 alterations rather than protein overexpression, so it does not test bemarituzumab directly. It adds weight to a shared lesson from both records, that a single FGFR2 selection label hides biologically distinct states, and that cell context may decide whether receptor-directed therapy engages the driver.

Abstract excerpt

Epithelial cancers disrupt tissue architecture and are often driven by mutations in genes that play important roles in normal epithelial morphogenesis. The intrahepatic biliary system is an epithelial tubular network that forms within the developing liver via the de novo initiation and expansion of apical lumens. Intrahepatic biliary tumors (intrahepatic cholangiocarcinoma) commonly harbor activating genomic alterations in the FGFR2 receptor tyrosine kinase, which plays important roles in epithelial morphogenesis in other developmental settings. Using a physiologic and quantitative 3D model we demonstrate that FGFR signaling is important for biliary morphogenesis and that oncogenic FGFR2 fusions and in-frame deletions disrupt biliary architecture. Importantly, we show that the trafficking of and signaling from the FGFR2 mutants, as well as their phenotypic impacts, are governed by the epithelial state of the cell. Unexpectedly, we also found that distinct tumor-driving FGFR2 mutants disrupt biliary morphogenesis in completely different and clinically relevant ways, informing our understanding of morphogenesis and tumorigenesis and highlighting the importance of convergent studies of both.

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2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.