Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is an established marker of normal and cancer stemlike cells. LGR5 has been implicated in promoting cancer cell plasticity that drives tumorigenesis, metastasis, and therapeutic resistance. LGR5 rapidly and constitutively internalizes and potentiates Wnt (Wingless/Int-1)/β-catenin and adhesion signaling pathways, though its precise mechanisms and interacting partners remain unresolved. An improved understanding of LGR5 signaling may provide invaluable insight into its intricate and important functions in cancer progression. Moreover, several LGR5-targeting therapies, including peptibody- and antibody-drug conjugates and bispecific antibodies, are showing promising efficacy and tolerability in colorectal cancer and other tumor types. This review discusses the cancer-related functions of LGR5 and explores the preclinical and clinical approaches to therapeutically target this enigmatic protein.
High et al. (2026) studied this question.