Abstract 2883: Cetuximab increases LGR5 expression and enhances efficacy of LGR5 antibody-drug conjugates in patient-derived models of colorectal cancer

Colorectal cancer (CRC) is the second-leading cause of cancer-associated deaths in the United States with a need for improved therapies. Antibody-drug conjugates (ADCs) are a rapidly expanding class of anticancer drugs that utilize monoclonal antibody (mAb) specificity to hone cytotoxic payloads to cancer cells. We generated ADCs targeting leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a cancer stem cell biomarker that is highly overexpressed in CRC. LGR5 ADCs demonstrated high specificity and efficacy in CRC cells and xenograft models without notable toxicity, although tumors eventually relapsed following treatment cessation. Interestingly, FDA-approved therapies targeting epidermal growth factor receptor (EGFR) have been shown to increase LGR5 expression in patient-derived models of CRC. This study therefore aims to determine the mechanisms of EGFR-mediated regulation of LGR5 expression and evaluate the therapeutic efficacy of EGFR-targeted therapies in combination with LGR5 ADCs for the improved treatment of CRC. We have demonstrated that cetuximab (CTX), an EGFR-targeting mAb approved for KRASWT metastatic CRC (mCRC), increases LGR5 protein levels independent of KRAS/PIK3CA mutational status in CRC cell lines, tumor organoids, and cell line-derived xenografts. Additionally, we identified a novel EGFR-LGR5 interaction that is enhanced by CTX treatment. Furthermore, we have generated a camptothecin-based LGR5 ADC (8E11-CPT2) utilizing site-specific conjugation technology that demonstrates target- and dose-dependent cytotoxicity in CRC cells and was well-tolerated. Importantly, combination treatment of 8E11-CPT2 with CTX in RASmut CRC patient-derived xenograft models significantly reduced tumor burden with notable regression in some mice and extended survival compared to LGR5 ADC and CTX monotherapies. These results demonstrate that combination treatments of LGR5 ADCs with CTX may prove more effective than ADC monotherapies in treating CRC and implicate expanded clinical utility for CTX to treat mCRCs with KRAS and/or PIK3CA mutations. Citation Format: Peyton High, Zhengdong Liang, Cara Guernsey-Biddle, Adela Aldana, Yukimatsu Toh, Qingyun Liu, Kendra S. Carmon. Cetuximab increases LGR5 expression and enhances efficacy of LGR5 antibody-drug conjugates in patient-derived models of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2883.