Biased antagonism of CXCR4 avoids antagonist tolerance
Ben Hitchinson1, Jonathan M Eby2, Xianlong Gao2,3
1Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
Abstract:
Repeated dosing of drugs targeting G protein-coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy of AMD3100, a competitive antagonist of the chemokine receptor CXCR4 that mobilizes leukemic blasts from the bone marrow into the blood to sensitize them to chemotherapy, is reduced after prolonged treatment. Tolerance to AMD3100 increases the abundance of CXCR4 on the surface of leukemic blasts, which promotes their rehoming to the bone marrow. AMD3100 inhibits both G protein signaling by CXCR4 and β-arrestin1/2-dependent receptor endocytosis. We demonstrated that biased antagonists of G protein-dependent chemotaxis but not β-arrestin1/2 recruitment and subsequent receptor endocytosis avoided tolerance. The peptide antagonist X4-2-6, which is derived from transmembrane helix 2 and extracellular loop 1 of CXCR4, limited chemotaxis and signaling but did not promote CXCR4 accumulation on the cell surface or cause tolerance. The activity of X4-2-6 was due to its distinct mechanism of inhibition of CXCR4. The peptide formed a ternary complex with the receptor and its ligand, the chemokine CXCL12. Within this complex, X4-2-6 released the portion of CXCL12 critical for receptor-mediated activation of G proteins but enabled the rest of the chemokine to recruit β-arrestins to the receptor. In contrast, AMD3100 displaced all components of the chemokine responsible for CXCR4 activation. We further identified a small molecule with similar biased antagonist properties to those of X4-2-6, which may provide a viable alternative to patients when antagonist tolerance prevents drugs from reaching efficacy.
Insights
Biased antagonists targeting the CXCR4 receptor avoid drug tolerance by selectively inhibiting G protein signaling, unlike traditional antagonists. This approach maintains drug efficacy for cancer therapy by preventing receptor accumulation and rehoming.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Repeated drug dosing targeting G protein-coupled receptors (GPCRs) can lead to antagonist tolerance, reducing therapeutic efficacy.
- AMD3100, a CXCR4 antagonist used to mobilize leukemic cells, exhibits reduced efficacy with prolonged treatment due to tolerance.
- Tolerance to AMD3100 increases surface CXCR4, promoting leukemic cell rehoming to the bone marrow.
Purpose of the Study:
- To investigate strategies for avoiding antagonist tolerance in CXCR4-targeted therapies.
- To identify novel antagonists that maintain efficacy upon repeated dosing.
- To elucidate the mechanisms underlying CXCR4 antagonist tolerance.
Main Methods:
- Assessing the efficacy of biased antagonists versus traditional antagonists in preventing AMD3100 tolerance.
- Characterizing the interaction of peptide antagonist X4-2-6 with CXCR4 and its ligand CXCL12.
- Evaluating the effect of biased antagonism on CXCR4 cell surface abundance and signaling pathways (G protein vs. β-arrestin).
- Identifying small molecules with biased antagonist properties.
Main Results:
- Biased antagonists that inhibit G protein-dependent chemotaxis but not β-arrestin recruitment prevented CXCR4 tolerance.
- The peptide antagonist X4-2-6 selectively inhibited G protein activation while allowing β-arrestin recruitment, avoiding CXCR4 accumulation and tolerance.
- AMD3100, a non-biased antagonist, displaced all CXCL12 components, leading to tolerance.
- A novel small molecule with biased antagonist properties was identified.
Conclusions:
- Biased antagonism represents a viable strategy to overcome CXCR4 antagonist tolerance.
- Targeting specific signaling pathways of GPCRs can maintain drug efficacy and prevent adverse effects like receptor accumulation.
- Biased CXCR4 antagonists may offer improved therapeutic alternatives for patients experiencing drug tolerance in cancer treatment.
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