Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 17, Pages 12572-12581Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00395
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Funding
- Wntrix Inc.
- Cancer Prevention and Research Institute of Texas [RP190542]
- Janice David Gordon for Bowel Cancer Research Endowment
- National Cancer Institute [R01CA226894]
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LGR4-6 are related receptors commonly upregulated in gastrointestinal cancers, with LGR5 being enriched in cancer stem cells. Targeting all three LGRs simultaneously is proposed for a more effective anti-tumor approach. A drug conjugate comprising an RSPO4 mutant and IgG1-Fc showed potent cytotoxic effects on cancer cells expressing any LGR, suppressing tumor growth without adverse effects.
LGR4-6 (leucine-rich repeat-containing G-protein-coupled receptors 4, 5, and 6) are three related receptors with an upregulated expression in gastrointestinal cancers to various extents, and LGR5 is enriched in cancer stem cells. Antibody-drug conjugates (ADCs) targeting LGR5 showed a robust antitumor effect in vivo but could not eradicate tumors due to plasticity of LGR5-positive cancer cells. As LGR5-negative cancer cells often express LGR4 or LGR6 or both, we reasoned that simultaneous targeting of all three LGRs may provide a more effective approach. R-spondins (RSPOs) bind to LGR4-6 with high affinity and potentiate Wnt signaling. We identified an RSPO4 furin domain mutant (Q65R) that retains potent LGR binding but no longer potentiates Wnt signaling. Drug conjugates of a peptibody comprising the RSPO4 mutant and IgG1-Fc showed potent cytotoxic effects on cancer cell lines expressing any LGR in vitro and suppressed tumor growth in vivo without inducing intestinal enlargement or other adverse effects.
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