FBXW7 Funktionsverlustmutationen treten in ~10–15% der SFB auf und führen zu einer Stabilisierung der m...
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| ID | BMA-FBXW7-CRC |
|---|---|
| Art | Therapeutische Relevanz |
| Status | reviewed 2026-05-04 | pending_clinical_signoff | actionability review required |
| Erkrankungen | DIS-CRC |
| Quellen | SRC-ESMO-CRC-2024 SRC-NCCN-COLON-2025 |
Fakten zur Handlungsfähigkeit
| Biomarker | BIO-FBXW7 |
|---|---|
| Variante | FBXW7 Funktionsverlustmutation im Kolorektalkarzinom (~10–15%); Onkoproteinstabilisierung/Widerstandsmarker; keine zugelassene FB XW7-gerichtete Therapie |
| Erkrankung | DIS-CRC |
| ESCAT-Stufe | IV |
| Empfohlene Kombinationen | FOLFOX oder FOLFIRI ± Bevacizumab oder Cetuximab (RAS/RAF-Wildtyp) — Standard 1L mCRC unabhängig vom FBXW7-Status, Pembrolizumab 200 mg q3w — 1L MSI-H/dMMR mCRK (KEYNOTE-177); Test MSI/MMR, nicht FB XW7 |
| Zusammenfassung der Beweise | FBXW7 loss-of-function mutations occur in ~10–15% of CRC and result in stabilization of multiple oncoproteins (NOTCH1/2, MYC, CCNE1, mTOR, JUN, MCL-1) that are normally targeted by the SCF-FBXW7 E3 ubiquitin ligase complex for proteasomal degradation. (1) WNT intersection: FBXW7 regulates β-catenin in some contexts; FBXW7 loss + APC mutation is common in CRC (both WNT pathway alterations, different nodes). (2) NOTCH pathway: FBXW7 loss stabilizes NOTCH — investigational gamma-secretase inhibitors (nirogacestat, AL101) target Notch processing, not downstream FBXW7 substrates. (3) Resistance implications: FBXW7 loss confers resistance to CDK4/6 inhibitors (via CCNE1 stabilization), anti-NOTCH agents, and potentially mTOR inhibitors (via mTOR stabilization). Not an independent predictive biomarker for any approved CRC therapy. (4) MSI-H co-occurrence: FBXW7 mutation is more common in MSI-H CRC (~20–25% MSI-H vs ~7% MSS); MSI-H remains the actionable determinant for immunotherapy (pembrolizumab). No approved targeted therapy exploits FBXW7 deficiency in CRC. ESCAT IV: no actionable ther... |
Anmerkungen
ESCAT IV: FBXW7 mutation in CRC has no current therapeutic implication beyond standard MSI/MMR/RAS/BRAF testing. Key points: (1) FBXW7 mutation is not a companion diagnostic for any approved agent. (2) It is a resistance predictor for CDK4/6 inhibitors (via CCNE1), relevant only if CRC were to enter CDK4/6 inhibitor trials. (3) When FBXW7 mutation is found on NGS, the clinically actionable step is to confirm MSI/MMR status (if not already done) — FBXW7 enrichment in MSI-H means the MSI-H status is the actionable finding. (4) Nirogacestat (gamma-secretase inhibitor, FDA-approved for desmoid tumor) targets Notch processing — mechanistically relevant to NOTCH substrate stabilization in FBXW7-mutant tumors, but desmoid-specific approval; no CRC data.
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