{"doi":"10.1101/2025.06.18.660406","title":"Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models","abstract":"SUMMARY 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 warranted strategies to improve ADC efficacy. Here we report cetuximab, an EGFR-targeting monoclonal antibody indicated for RAS WT 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 RAS MUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggests a broader clinical use for cetuximab in treating RAS MUT CRC.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556466,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":701949,"name":"Zhengdong Liang","orcid":"0000-0003-4861-3941","position":1,"is_corresponding":false},{"id":1238421,"name":"Cara Guernsey-Biddle","orcid":"0000-0001-6087-1228","position":2,"is_corresponding":false},{"id":985415,"name":"Shraddha Subramanian","orcid":"0000-0002-7351-5924","position":3,"is_corresponding":false},{"id":1262214,"name":"Yueh-Ming Shyu","orcid":"0000-0002-3338-2020","position":4,"is_corresponding":false},{"id":1249357,"name":"Adela M. Aldana","orcid":null,"position":5,"is_corresponding":false},{"id":330788,"name":"Yukimatsu Toh","orcid":"0000-0001-8409-3512","position":6,"is_corresponding":false},{"id":330789,"name":"Kendra S. Carmon","orcid":"0000-0002-3244-6096","position":7,"is_corresponding":false},{"id":1238420,"name":"Peyton C. High","orcid":"0000-0002-4318-4490","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T02:55:08.896385Z","pmid":"40667242","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}