FBXW7 in gastrointestinal cancers: from molecular mechanisms to therapeutic prospects

Abstract

F-box and WD repeat domain-containing 7 (FBXW7), formerly known as hCdc4, hAGO Fbw7, or SEL10, plays a specific recognition function in SCF-type E3 ubiquitin ligases. FBXW7 is a well-established cancer suppressor gene that specifically controls proteasomal degradation and destruction of many key oncogenic substrates. The FBXW7 gene is frequently abnormal in human malignancies especially in gastrointestinal cancers. Accumulating evidence reveals that mutations and deletions of FBXW7 are participating in the occurrence, progression and treatment resistance of human gastrointestinal cancers. Considering the current therapeutic challenges faced by gastrointestinal cancers, elucidating the biological function and molecular mechanism of FBXW7 can provide new perspectives and references for future personalized treatment strategies. In this review, we elucidate the key molecular mechanisms by which FBXW7 and its substrates are involved in gastrointestinal cancers. Furthermore, we discuss the consequences of FBXW7 loss or dysfunction in tumor progression and underscore its potential as a prognostic and therapeutic biomarker. Lastly, we propose potential therapeutic strategies targeting FBXW7 to guide the precision treatment of gastrointestinal cancers.

Keywords: FBXW7; biomarker; gastrointestinal cancers; molecular mechanism; therapeutic strategies.

FIGURE 1

Major molecular markers of gastrointestinal cancers. The key molecular markers for esophageal cancer include HER2 amplification or overexpression, PD-L1, EGFR, and VEGFR (Liu et al., 2020; Zhou and Hofstetter, 2020; Wang et al., 2025). For pancreatic cancer, the main molecular markers are NTRK fusion, BRCA1/2 mutations, KRAS mutations, BRAF mutations, and MSI (Collisson et al., 2019; Buscail et al., 2020; Wang S. et al., 2021; Schlick et al., 2021). Molecular markers for cholangiocarcinoma mainly include MSI, HER-2 amplification or overexpression KRAS mutations,IDH1/2 mutations, FGFR2 fusion and NTRK fusion (Rodrigues et al., 2021; Pavicevic et al., 2022; Kam et al., 2021). The major molecular markers for colorectal cancer include MMR/MSI, RAS/BRAF mutations, NTRK fusion, POLE/POLD1 mutations, PI3K mutations, and HER2 amplification or overexpression (Martelli et al., 2022; Taieb et al., 2019; Sepulveda et al., 2017). The main molecular markers for gastric cancer include MSI, PD-L1,HER-2 amplification or overexpression, Claudin18.2, TMB, and EBV (Guan et al., 2023; Joshi and Badgwell, 2021; Elimova et al., 2015). So far the molecular alterations in hepatocellular carcinoma have not led to effective treatments (Nault and Villanueva, 2021). In the figure we show several promising molecular markers such as ctDNA, ncRNA, TERT promoter mutation and MSI (Nault and Villanueva, 2021; Llovet et al., 2018; Chan et al., 2024a).

FIGURE 2

Structure and function of FBXW7. The FBXW7 gene is located on 4q31.3 and encodes three FBXW7 isoforms: FBXW7α, FBXW7β, and FBXW7γ. Despite differences at their N-terminal regions, all three isoforms share dimerization domains, F-box domains, and WD40 repeat domains. FBXW7 primarily targets substrates such as TGF-β, c-Jun, Cyclin E, c-Myc, Notch1, MCL-1, YAP, and mTOR for degradation. Additionally, the expression of FBXW7 is regulated by p53, non-coding RNAs, LSD1, ERK1/2, USP28, HES5, and C/EBPδ.

FIGURE 3

Interaction of FBXW7 with signaling pathways and key molecules in gastrointestinal cancers. (1) FBXW7 directly targets EGFR and SHOC2, blocking the activation of the MAPK signaling pathway. ERK1/2 promotes FBXW7 phosphorylation, further activating the MAPK pathway. (2) FBXW7 directly targets β-catenin, inhibiting the activation of the Wnt/β-catenin signaling pathway. (3) FBXW7 directly targets Nox1, PTEN, and mTOR, inhibiting the activation of the Akt/mTOR signaling pathway. (4) FBXW7 degrades MCL-1, thereby promoting apoptosis. (5) FBXW7 targets Notch1/NICD, inhibiting MAPK signaling. The degradation of Notch1/NICD inhibits cell proliferation. (6) FBXW7 mediates Cyclin E degradation, maintaining a normal cell cycle. (7) MicroRNA-770, MiR-92a-3p, MiR-27a, and MiR-223 inhibit FBXW7 expression.

FIGURE 4

Strategies for targeting FBXW7 in the treatment of cancers (A). Inhibition of regulators such as miRNA and ERK can upregulate the expression of FBXW7. Additionally, inhibiting FBXW7 downstream substrates, such as MCL-1 and mTOR, may reduce cancer cell proliferation and drug resistance (B). Inhibiting FBXW7 expression in cancer stem cells (CSCs) can awaken cell cycle-arrested CSCs, making them more sensitive to treatment.