Base Editing Uncovers Vulnerability in WNT-Driven Colorectal Cancer

The WNT–β-catenin pathway is one of the best-established drivers of colorectal cancer. More than 80% of colorectal tumours carry truncating mutations in APC, which disable the β-catenin destruction complex, allowing β-catenin to accumulate and activate oncogenic transcription. Despite decades of research, the pathway has remained notoriously difficult to target therapeutically.

To dissect the molecular architecture of the destruction complex, researchers at Stanford University performed large-scale adenine and cytosine base editor screens across the endogenous CTNNB1, APC, AXIN1 and GSK3B genes. Rather than knocking genes out, the approach introduced precise transition mutations at most coding residues, allowing the team to measure how individual amino acid changes affected WNT signalling in living human cells.

The screens recovered many known cancer-associated mutations but also uncovered approximately 150 previously unreported functional variants. Among the most important findings was evidence that β-catenin itself helps stabilise the destruction complex when APC is truncated. The researchers describe this as a substrate-assisted autoregulatory mechanism, in which β-catenin functions not only as the substrate targeted for degradation but also as a structural scaffold that supports assembly of the residual destruction complex in APC-mutant cells.

This insight revealed a potential therapeutic opportunity. The study showed that strengthening the interaction between β-catenin and AXIN1 restored destruction complex function and reduced the growth of colorectal cancer cells carrying APC mutations, suggesting that this protein interface could represent a previously unrecognised drug target.

Although the work remains preclinical and was performed in cultured cells, it demonstrates how CRISPR base editing can be used not only to validate disease-associated variants but also to systematically map functional protein interfaces and uncover new therapeutic vulnerabilities that may be inaccessible through conventional genetic screening.

The study was led by Murugesh Padmanarayana, Ganesh V. Pusapati and Rajat Rohatgi at Stanford University School of Medicine. It was published in Nature Genetics on 2 July 2026.