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Regorafenib
Stivarga
Multi-kinase inhibitor (VEGFR/KIT/PDGFR/FGFR/RAF)
Evidence Score
60
Broad-spectrum multi-kinase inhibitor targeting VEGFR1-3 (KDR; anti-angiogenic), KIT, PDGFR-α/β, FGFR1/2, and RAF1/BRAF. FDA-approved for advanced GIST after failure of imatinib and sunitinib, based on the GRID Phase 3 trial (NCT01271712; Demetri et al., Lancet 2013, PMID 23099011; n=199; median PFS 4.8 vs 0.9 months, HR 0.27, p<0.0001 vs placebo; crossover design confirmed strong signal). In SDH-deficient GIST specifically, regorafenib covers two mechanistically complementary axes: (1) Anti-angiogenic VEGFR1-3 blockade — SDH loss drives constitutive HIF-1α/2α stabilization via succinate-mediated PHD inhibition, which transcriptionally upregulates VEGFA, making VEGFR inhibition a cross-tumor-type anti-angiogenic anchor. (2) FGFR1/2 inhibition — aberrant FGF3/FGF4 autocrine FGFR1 signaling is the dominant growth driver in SDH-deficient GIST, arising from CIMP-driven hypermethylation of CTCF-binding insulator elements at the FGF3/FGF4 locus; this mechanism was validated by rogaratinib (pan-FGFR inhibitor) achieving 41.7% ORR in a Phase 2 trial (Nat Med 2026, PMID 42191879). Regorafenib inhibits FGFR1 (IC50 ~130 nM) and FGFR2 (~170 nM) at clinically achievable concentrations, providing a mechanistically relevant — if less potent — FGFR dimension on top of its anti-angiogenic activity. SDH-deficient GIST is inherently KIT/PDGFRA-independent (wild-type for both); regorafenib's activity in this subtype is therefore driven by VEGFR anti-angiogenesis and FGFR1/2 inhibition rather than KIT blockade.
Downstream of HIF activation, VEGF/VEGFR2 signaling drives tumor angiogenesis — the formation of new blood vessels that supply the tumor with oxygen and nutrients.
Upstream event:
HIF-mediated VEGFA transcriptional activation
Downstream effects:
Metabolic reprogramming from SDH loss activates the PI3K/AKT/mTOR signaling axis, promoting cell growth, proliferation, and survival. Multiple upstream inputs converge on mTOR.
Upstream event:
HIF-mediated growth factor signaling + metabolic stress + AMPK dysregulation
Downstream effects:
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:
KDR
VEGF receptor 2 (VEGFR2)
Primary VEGF receptor on endothelial cells. Target of sunitinib, regorafenib, and other multi-kinase inhibitors.
UniProt: P35968
KIT
KIT proto-oncogene receptor tyrosine kinase
Primary oncogene in most GISTs, but SDH-deficient GISTs typically have wild-type KIT. Some residual KIT signaling may persist.
UniProt: P10721
FGFR1
Fibroblast growth factor receptor 1
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
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
Tumor Type Applicability
Approved Indications
- Advanced GIST (third-line, after imatinib and sunitinib failure)
- Metastatic colorectal cancer
- Hepatocellular carcinoma
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.
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.