Language
English
Publication Date
9-18-2025
Journal
Cell Reports Medicine
DOI
10.1016/j.xcrm.2025.102363
PMID
40972582
Abstract
Colorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warrants strategies to improve ADC efficacy. Here, we report that cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody indicated for RASWT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well tolerated and significantly inhibits tumor growth. Importantly, cetuximab in combination with LGR5 ADCs results in enhanced tumor inhibition or regression versus single-agent treatment and extends survival in RASMUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggest a broader clinical use for cetuximab in treating RASMUT CRC.
Keywords
EGFR, LGR5, antibody-drug conjugate, cetuximab, colorectal cancer, combination treatment
Published Open-Access
yes
Recommended Citation
High, Peyton C; Liang, Zhengdong; Guernsey-Biddle, Cara; et al., "Cetuximab Increases LGR5 Expression and Augments LGR5-Targeting Antibody-Drug Conjugate Efficacy in Patient-Derived Colorectal Cancer Models" (2025). The Brown Foundation: Institute of Molecular Medicine. 13.
https://digitalcommons.library.tmc.edu/molecular_med/13