Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

Cancer research · Colorectal cancer · BRAF

Degradation of the RNA-binding protein HuR by the molecular glue degrader dHuR suppresses colorectal cancer harboring BRAF mutations

BRAF gain‑of‑function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA‑binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran‑tethered composite surface to recruit HuR as a neosubstrate by engaging its β‑hairpin G‑loop degron, as revealed by the cryo‑electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF‑mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF‑mutant CRC.

BRAF‑mutant colorectal cancer represents an aggressive subtype with poor survival and limited responses to current targeted therapies. The discovery of a molecular glue degrader that eliminates the post‑transcriptional regulator HuR and down‑regulates BRAF expression offers a novel therapeutic approach that can overcome resistance mechanisms and improve treatment outcomes.

Evidence level: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.

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