Wnt / β-catenin
Wnt/β-catenin is a developmental pathway hijacked by colorectal cancer. Normally a destruction complex keeps β-catenin low; losing APC lets it flood the nucleus and drive growth genes.
Without Wnt, β-catenin is phosphorylated by the destruction complex (APC, AXIN, GSK3β, CK1) and degraded. Wnt binding to Frizzled/LRP5/6 disables the complex; β-catenin accumulates, enters the nucleus, and with TCF/LEF drives MYC, cyclin D1, LGR5, AXIN2. APC loss initiates ~80% of colorectal cancers; CTNNB1 mutations occur in HCC, endometrial, and desmoid tumours; RNF43/RSPO alterations define a ligand-dependent subset. Wnt is also immunosuppressive (excludes dendritic cells). Drugs have been hard: porcupine inhibitors for RSPO/RNF43 tumours, tankyrase inhibitors, and nirogacestat (gamma-secretase, desmoid) are the closest.
In one picture
β-catenin is a messenger constantly being shredded by a committee (APC and friends). A Wnt signal tells the committee to stand down. Colorectal cancer fires the committee (APC loss), so the messenger runs unchecked into the nucleus.
Diagram
top- Porcupine inhibitors (RSPO-fusion / RNF43-mutant tumours, trials)
- Gamma-secretase inhibitor nirogacestat in desmoid tumours (approved 2023)
- Tankyrase inhibitors (preclinical/early)
- Indirect: chemoprevention with aspirin/COX-2 in Lynch and FAP
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