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Abstract Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. One of the primary challenges in treating CRC is therapy resistance thought to be mediated by cancer stem cells (CSCs), a subpopulation of cancer cells with infinite replicative potential that can differentiate to drive tumorigenesis and disease relapse. Antibody-drug conjugates (ADCs) are amongst the fastest growing classes of anticancer drugs and utilize the specificity of monoclonal antibodies (mAbs) to hone cytotoxic payloads to cancer cells. We generated ADCs directed against leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-defined biomarker of CSCs that is highly overexpressed in CRCs. LGR5 ADCs demonstrated high specificity and efficacy in CRC cells and xenograft models, though tumor relapse after treatment withdrawal was a major obstacle. Interestingly, FDA-approved therapy targeting epidermal growth factor receptor (EGFR) has been shown to increase LGR5 mRNA expression levels in patient-derived models of CRC. This study aims to determine the mechanism of EGFR-mediated regulation of LGR5 expression and evaluate the therapeutic efficacy of combination treatments targeting EGFR and LGR5 for the improved treatment of CRC. To first analyze the effect of EGFR inhibition on LGR5 expression, a panel of CRC cell lines of different KRAS and PI3CKA mutational statuses were treated with FDA-approved EGFR-targeted mAbs or small molecule inhibitors. LGR5 protein expression was shown to be upregulated by EGFR-targeted therapies in a dose- and time-dependent manner, independent of mutation status. Notably, treatment with EGF, MEK1/2 inhibitor trametinib, and EGFR-directed siRNA all resulted in concomitant reduction in EGFR and LGR5 protein levels, suggesting EGFR and LGR5 are co-degraded. Co-immunoprecipitation and immunocytochemistry experiments identified a novel EGFR-LGR5 interaction and co-internalization mechanism in CRC cells, respectively. Furthermore, we showed EGFR-LGR5 interaction is enhanced by treatment with the EGFR-targeting mAb, cetuximab (CTX). To evaluate efficacy of combination therapies targeting EGFR and LGR5, CRC cells were treated with LGR5 ADCs with or without CTX. Importantly, we showed CTX significantly enhanced the potency of LGR5 ADCs incorporating different classes of cytotoxic payloads. These results suggest combining LGR5 ADCs with EGFR inhibitors may be a more effective approach for the treatment of CRC and eliminating CSCs to overcome resistance and relapse. Citation Format: Peyton C. High, Zhengdong Liang, Kendra S. Carmon. EGFR inhibitors increase LGR5 expression and enhance potency of LGR5 antibody-drug conjugates targeting colorectal cancer stem cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4552.
High et al. (Fri,) studied this question.