# A Cereblon signaling network in Wnt-driven cancers

> **NIH CA R01** · DARTMOUTH COLLEGE · 2026 · $655,614

## Abstract

A Cereblon Signaling Network in Wnt-driven Cancers
Abstract
The long-term objective of this study is to investigate how Cereblon (CRBN) regulates the Wnt signal transduction
pathway and to demonstrate how this can be exploited to target Wnt-driven colorectal cancers (CRCs). Wnt
signaling is essential for intestinal stem cell maintenance and aberrant activation of this pathway drives the
initiation and progression of nearly all CRCs. To date, no drugs that inhibit the Wnt pathway have been FDA-
approved, partly due to the lack of druggable targets that can bypass common Wnt pathway mutations in CRC.
In a conceptual breakthrough, our recently published findings reveal that Cereblon (CRBN), the substrate
receptor of the CRL4CRBN E3 ubiquitin ligase that is a drug target in hematological malignancies, plays a critical
role in Wnt signal transduction. We found that CRBN promotes the degradation of a subset of substrates,
including Casein kinase 1α (CK1α), a negative regulator of Wnt signaling and a key component of the β-Catenin
destruction complex. Moreover, Wnt stimulation induces the interaction of CRBN with CK1α to promote its
ubiquitination and degradation. Furthermore, we showed that the role of CRBN in Wnt signaling is conserved in
human cells, mouse intestinal organoids, zebrafish, and Drosophila. These studies demonstrate the first
endogenous mechanism of CRBN regulation and provide a novel means of controlling Wnt pathway activity, with
relevance for animal development and disease. The goal of this project is to use in vitro, ex vivo, and in vivo
approaches to gain a better understanding of how the clinically relevant anti-cancer target, CRBN, promotes Wnt
signal transduction. The three specific aims are to: 1) Identify the mechanisms by which Wnt stimulation activates
CRBN; 2) Identify Wnt-stimulated CRBN interactors that regulate tumorigenesis; and 3) elucidate the role of
CRBN in Wnt-dependent cancer progression. Because CRBN is a well-studied target for the

## Key facts

- **NIH application ID:** 11285162
- **Project number:** 5R01CA281002-04
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Yasmath  Ahmed; ETHAN  LEE; DAVID J ROBBINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $655,614
- **Award type:** 5
- **Project period:** 2023-03-10T00:00:00 → 2028-02-29T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11285162

## Citation

> US National Institutes of Health, RePORTER application 11285162, A Cereblon signaling network in Wnt-driven cancers (5R01CA281002-04). Retrieved via AI Analytics 2026-05-17 from https://api.ai-analytics.org/grant/nih/11285162. Licensed CC0.

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