Title : Molecular glue-mediated degradation of PELO reveals a novel therapeutic opportunity in microsatellite instability-high colorectal cancer

Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is characterized by defective DNA mismatch repair and widespread genomic instability, creating unique therapeutic vulnerabilities. Although immune checkpoint blockade has improved clinical outcomes for a subset of MSI-H CRC patients, many patients fail to achieve durable responses, highlighting the need for novel targeted therapies. Through analysis of genetic dependency datasets and experimental validation, we identified PELO, a key ribosome rescue factor involved in mRNA quality control, as a highly expressed and selectively essential gene in MSI-H CRC. To evaluate its therapeutic potential, we employed genetic loss-of-function approaches in MSI and microsatellite stable (MSS) CRC models and assessed tumor growth in vitro and in vivo. Furthermore, we established a structurally diverse molecular glue compound library and performed drug screening to identify small molecules capable of inducing PELO degradation. Our results demonstrated that PELO suppression significantly inhibited proliferation and tumor growth in MSI CRC models, whereas MSS CRC cells exhibited substantially lower sensitivity, indicating a selective dependency on PELO in MSI tumors. In addition, we identified Cpd47 as a potent PELO degrader that promotes proteasome-dependent degradation of PELO. Cpd47 selectively reduced the viability of MSI CRC cells while exhibiting minimal effects on MSS CRC cells. Mechanistically, both PELO depletion and Cpd47 treatment activated unfolded protein response signaling, cellular stress pathways, and apoptosis. Collectively, these findings establish PELO as a novel synthetic lethal vulnerability in MSI-H colorectal cancer and provide proof-of-concept evidence that molecular glue-mediated PELO degradation represents a promising therapeutic strategy. 

Dr. Chen Wang is an Associate Research Fellow at Shanghai Tongren Hospital, specializing in the discovery and validation of novel therapeutic targets, drug sensitization, and resistance mechanisms in gastrointestinal cancers. She received her PhD from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, in 2019 and subsequently completed postdoctoral training at City of Hope, The Wistar Institute, and The University of Texas MD Anderson Cancer Center. Her research integrates functional genomics, epigenetics, and cancer therapeutics, with expertise in CRISPR screening, base editing, next-generation sequencing technologies, and bioinformatics analysis. Dr. Wang has published over 30 peer-reviewed articles, including first-author papers in Nature Communications, Theranostics, and Journal of Medicinal Chemistry.