GoKawiilCRC harbouring BRAF mutations (approximately 10% of cases) represents one of the most aggressive and therapeutically challenging CRC subtypes4, with a median survival of less than 12 months under current therapies3. Unlike BRAF-mutant melanoma, where BRAF inhibitors (for example, vemurafenib and encorafenib) show remarkable efficacy, BRAF-mutant CRC exhibits intrinsic resistance due to EGFR-dependent feedback reactivation of the MAPK pathway. Although the US Food and Drug Administration (FDA)-approved combination of encorafenib (a BRAF inhibitor (BRAFi)) + cetuximab (an anti-EGFR antibody) improves response rates (20–26% versus 5% with BRAFi alone)5,6, most patients derive no benefit, and responders typically relapse within 4–6 months6. Consequently, more than 75% of patients with BRAF-mutant CRC lack durable treatment options7, underscoring the urgent need for novel therapeutic modalities that overcome resistance or alternative targeting strategies for BRAF or its critical co-factors.
The human RNA-binding protein HuR is encoded by the gene ELAV-like RNA-binding protein 1 (ELAVL1; also known as HUR) and binds to AU-rich elements within the introns or 3′ untranslated regions of target mRNAs, thereby regulating pre-mRNA processing, mRNA stability and translation8,9. HuR has a critical role in modulating mRNA stability and translational control, serving as a key post-transcriptional regulator of specific RNAs across both physiological and pathological contexts, particularly in cancer progression10,11. HuR is frequently overexpressed and/or abnormally enriched in the cytoplasm of cancer cells. Its aberrant expression is associated with high tumour grades and poor prognoses across a spectrum of malignancies, including CRC12. HuR enhances the expression of proteins that drive cancer progression, such as vascular endothelial growth factor (VEGF) and cell cycle regulators, particularly in response to stresses such as oncogenic mutations and chemotherapy or targeted therapies10,13,14. Through its pleotropic effects, HuR promotes tumour growth, invasion, angiogenesis and resistance to therapeutic agents, making it an important target for cancer therapeutics15. The discovery of small molecules and small interfering RNAs that inhibit the function of HuR have provided proof of concept for potential therapeutic benefit of targeting HuR in many cancer types, such as colorectal, pancreatic, renal, ovarian, breast, liver and lung cancers, as well as malignant peripheral nerve sheath tumour16,17,18,19,20,21,22,23,24,25. However, none of these drug candidates has been advanced to clinical development to date, owing to poor potency or lack of efficient delivery to the tumour26.
Molecular glue degraders (MGDs), a novel class of chemical compounds, have recently emerged as a promising strategy for selectively targeting and degrading disease-causing proteins, including those considered ‘undruggable’. By chemically inducing ternary complex formation between a target protein and a ubiquitin E3 ligase, MGDs trigger proximity-driven ubiquitination and subsequent degradation of the target protein. Of note, recent breakthroughs have expanded the cereblon (CRBN)-based MGD target landscape. Beyond classical immunomodulatory drugs (IMiDs) such as thalidomide analogues—which target the transcription factors IKZF1, IKZF3, ZFP91, ZMYM2 and SALL4 (refs. 27,28,29,30)—MGDs have also been identified against additional zinc-finger proteins (for example, IKZF2 and WIZ)31,32, kinases (for example, CK1α)33 and scaffold proteins (for example, GSPT1)34. In addition, cryo-electron microscopy (cryo-EM) structural studies of CRBN–MGD–neosubstrate complexes have revealed critical molecular determinants for ternary complex formation35,36,37, including β-hairpin stabilization and hydrophobic ‘glue patches’. Despite these advances, fundamental challenges persist in rational MGD development. Serendipity still drives most discoveries owing to limited predictive tools. This bottleneck stems from the transient nature of MGD-induced protein–protein interactions and the lack of universal structural signatures for ‘glueable’ target interfaces. Recent computational efforts using deep learning platforms (for example, AlphaFold38) for interface prediction show promise but require experimental validation.
Fortunately, emerging proteomic technologies are now enabling systematic discovery of MGD-responsive targets. Here we utilized large-scale proteomic profiling of cells treated with rationally designed CRBN modulators and identified MGDs targeting HuR. Mechanism-of-action studies showed that dHuRs function as molecular glues to induce a CRBN–MGD–HuR ternary complex, leading to the polyubiquitination and proteasomal degradation of HuR. Through a series of bioinformatics analyses, in vitro cell-based assays and in vivo models, we discovered that BRAF-mutated CRC cells are particularly sensitive to the treatment of dHuRs. The mechanism leading to this activity is at least in part due to the effects of HuR degradation on BRAF RNA splicing and decreased BRAF protein level. The anti-proliferative effect of HuR degradation is also demonstrated in BRAFi-resistant cancer cells and is associated with decreased oncogenic protein BRAF and EGFR and sustained decrease of MAPK pathway signalling as measured by p-ERK level. This combination of HuR degradation with EGFR–BRAF–MEK inhibition resulted in synergistic antitumour effects. These data support the development of dHuR in BRAF-mutated CRC.