# BET degraders for improving colorectal cancer therapy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $416,526

## Abstract

PROJECT SUMMARY/ABSTRACT
 Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the US. Developing novel
and more effective CRC therapies is an unmet biomedical need as most of advanced and metastatic CRCs that
progress after initial therapies respond poorly to therapeutic treatment. The bromodomain and extra-terminal
domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of key oncogenic
proteins that drive CRC initiation and progression. Targeting the BET family proteins using small-molecule
inhibitors has emerged as a promising therapeutic approach. However, BET inhibitors (BETi) as single agents
are generally ineffective against epithelial cancers including CRCs. The molecular mechanisms underlying the
anticancer activity of BET-targeting agents are not well understood. Recently, a new class of agents that induce
rapid degradation of BET proteins has been developed. Our preliminary studies reveal that two such BET
degraders (BETd), BETd260 and BETd246, are much more potent than other BET-targeting agents in CRC cells
and patient-derived xenografts (PDXs). We identified a novel, on-target mechanism of action of BETd in
transcriptionally activating Death Receptor 5 (DR5), a key component of the extrinsic apoptotic pathway.
Importantly, the induction of DR5 is essential for the cell-killing and chemosensitization effects of BETd, and
responsible for increased BETd sensitivity in a subset of CRCs with an activating mutation in Speckle-type POZ
protein (SPOP), a subunit of the E3 ubiquitin ligase of BET proteins. Furthermore, our data suggest BETd have
robust immunogenic effects by inducing DR5-mediated immunogenic cell death (ICD). A combination of
BETd260 and anti-PD-1 antibody was well tolerated and nearly eradicated mouse CT26 syngeneic tumors in a
DR5-dependent manner. Based on these findings, we hypothesize that BETd improve CRC therapies by
inducing DR5-mediated CRC cell killing and antitumor immunity. Aim 1. Identify the mechanism and biomarkers
of the potent anticancer activity of BETd in CRC cells; Aim 2. Determine the therapeutic efficacy of BETd against
therapy-refractory and metastatic CRCs; Aim 3. Delineate and harness the immunogenic effects of BETd to
improve CRC therapies. The proposed studies are expected to provide new mechanistic insights and establish
key preclinical parameters for using BETd to develop precision and personalized therapies against
therapy-refractory and incurable CRCs. In the long run, these studies may lead to new and improved therapies
against CRCs and other types of cancer.

## Key facts

- **NIH application ID:** 10372054
- **Project number:** 5R01CA248112-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Lin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,526
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372054

## Citation

> US National Institutes of Health, RePORTER application 10372054, BET degraders for improving colorectal cancer therapy (5R01CA248112-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10372054. Licensed CC0.

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