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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

Tumor Type Applicability

GIST
Not FDA Approved
Clinical Trials
NCT04595747
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.