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Rogaratinib

Pan-FGFR inhibitor (FGFR1/2/3/4)

Evidence Score

76

clinical trial
Mechanism of Action

Potent, selective oral pan-FGFR kinase inhibitor. In SDH-deficient GIST, SDH loss drives genome-wide DNA hypermethylation via succinate inhibition of TET dioxygenases. This hypermethylation disrupts CTCF-binding insulator elements flanking the FGF3/FGF4 gene locus, causing aberrant overexpression of these oncogenic FGF ligands and establishing an autocrine FGFR1 signaling loop that drives tumor growth. Rogaratinib blocks FGFR1/2/3/4 kinase activity, interrupting this epigenetically-driven autocrine signaling cascade selectively in SDH-deficient cells. In a Phase 2 trial (NCT04595747, n=24), rogaratinib achieved an objective response rate of 41.7% (10 partial responses) and a median progression-free survival of 31.0 months — the strongest prospective efficacy signal reported for advanced SDH-deficient GIST. Key toxicities: hyperphosphatemia (on-target, from FGFR1-mediated FGF23/phosphate regulation), fatigue, and diarrhea. Pharmacodynamic monitoring via serum phosphorus validates FGFR1 target engagement (Merriam et al., Nat Med 2026, PMID: 42191879; NCT04595747).

Pathway Connections
Epigenetic Dysregulation

Succinate inhibits TET family DNA demethylases and Jumonji-domain histone demethylases, causing global DNA and histone hypermethylation. This silences tumor suppressors and blocks differentiation.

Upstream event:

Succinate inhibits TET1/2/3 and KDM histone demethylases

Downstream effects:

DNA hypermethylation (CIMP phenotype)5-hydroxymethylcytosine lossTumor suppressor silencingHistone hypermethylationDifferentiation block
FGFR Signaling (Epigenetic Insulator Disruption)

SDH-loss-driven genome-wide DNA hypermethylation disrupts CTCF-binding insulator elements flanking the FGF3/FGF4 gene locus, causing aberrant, high-level transcription of these oncogenic FGF ligands. The ligands activate an autocrine/paracrine FGFR1 signaling loop that promotes SDH-deficient tumor growth. This mechanism was established in GIST by a 2026 Phase 2 trial of rogaratinib (Nat Med 2026, PMID 42191879).

Upstream event:

Succinate-driven TET inhibition → genome-wide DNA hypermethylation → CTCF insulator disruption → aberrant FGF3/FGF4 activation

Downstream effects:

Autocrine FGFR1 signalingTumor cell proliferation and survivalFGF3/FGF4 as pharmacodynamic biomarkersHyperphosphatemia as on-target FGFR1 engagement markerSelective vulnerability in SDH-deficient vs. SDH-intact tumors
Molecular Targets

FGFR1

Fibroblast growth factor receptor 1

downstream

Receptor tyrosine kinase that mediates FGF3/FGF4 signaling. In SDH-deficient GIST, aberrant FGF3/FGF4 overexpression driven by DNA-hypermethylation-induced insulator disruption activates FGFR1 in an autocrine loop. Target of rogaratinib (pan-FGFR inhibitor) in the Phase 2 trial showing 41.7% ORR (Nat Med 2026, PMID 42191879).

UniProt: P11362

FGFR2

Fibroblast growth factor receptor 2

downstream

Second FGFR subtype co-expressed in SDH-deficient tumors; pan-FGFR inhibitors including rogaratinib and erdafitinib target FGFR1-4. Inhibited by rogaratinib in the SDH-deficient GIST Phase 2 trial and by erdafitinib (FDA-approved pan-FGFR, urothelial carcinoma).

UniProt: P21802

Quick Facts
Not FDA Approved
Evidence

Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.

Coming in Phase 3

For research exploration only — not medical advice. Consult your doctor before acting on any information.

AI Analysis

Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.