Command Palette

Search for a command to run...

Preprint WatchModerateOctober 14th, 2026

An RFX-driven ciliogenic cell state defines ex vivo FGFR-inhibitor sensitivity in colorectal cancer

Kralickova, L.; Miglino, N.; Esposito, C.; Pfaendler, R.; Wegmann, R.; Ballesteros Cuartero, P.; Mena, J.; Panebianco, F.; Boos, L. A.; Richter, U.; Rahimzadeh, P.; Mehra, T.; Koelzer, V. H.; Piscuoglio, S.; Wicki, A.; Snijder, B.

A cilium-linked, RFX-driven transcriptional cell state predicts ex vivo sensitivity to FGFR inhibition in colorectal cancer, offering a tumour-state stratifier where genomic alteration does not identify responders.

Moderate contradiction

2 prior failures

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

This preprint proposes a transcriptional cell state, rather than a genomic alteration, as the selector for FGFR inhibitor sensitivity in colorectal cancer. Claidex holds two FGFR2 failures that bear directly on that proposal. In bemarituzumab-fgfr2b-gastric-gej-fortitude-102-phase3-efficacy-termination the programme selected patients by FGFR2b protein overexpression and still failed on efficacy at Phase 3, and in bemarituzumab-fgfr2-fgfr2b-overexpressing-solid-tumors-phase1b2-strategic-termination the same overexpression-selected approach was discontinued earlier. The shared lesson is that expression-level selection on this target has already proved insufficient once at registrational scale, so a new state-based stratifier needs prospective validation against a hard clinical endpoint before it is treated as a patient-selection tool rather than a preclinical correlate.

Abstract excerpt

Genomic stratification leaves most patients with colorectal cancer (CRC) without opportunities for targeted therapy. Seeking tumour state-linked drug sensitivities, we combined image-based ex vivo drug profiling with matched transcriptomics in 127 prospectively collected patient biopsies across CRC stages and molecular subtypes. Network-level integration identified a ciliogenic cell state defined by upregulation of cilia related genes with selective sensitivity to the FGFR inhibitor erdafitinib. This ciliogenic signature was associated with poor progression-free survival (hazard ratio 2.28; adjusted p=0.0098), even in early-stage colorectal cancer. Furthermore, knockdown of the transcriptional regulators RFX2 and RFX3, upstream of the ciliogenic cell state, attenuated erdafitinib sensitivity. Orthogonal bulk and single-cell analyses across normal, primary and metastatic tissues contextualised the ciliogenic programme along a transition from canonical epithelial states towards fetal and non-canonical tumour states, concomitant with Wnt-related remodelling, FGFR1/FGFR2 upregulation, and loss of intestinal epithelial identity. Together, these findings define a tumour-intrinsic ciliogenic cell state as a feature of CRC progression, revealing a patient-stratified repurposing opportunity for targeted therapy beyond the current CRC treatment paradigms.

Matching Claidex post-mortems

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.