Research ArticleGPCR SIGNALING

Biased antagonism of CXCR4 avoids antagonist tolerance

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Science Signaling  16 Oct 2018:
Vol. 11, Issue 552, eaat2214
DOI: 10.1126/scisignal.aat2214

The right kind of bias

AMD3100, an antagonist of the chemokine receptor CXCR4, prevents the accumulation of leukemic cells in the bone marrow, which promotes the efficacy of chemotherapeutic agents. However, tolerance to AMD3100 can develop, which leads to receptor accumulation on the cell surface and retention of cells in the bone marrow. Hitchinson et al. showed that a peptide derived from CXCR4 avoided the development of tolerance by acting as a biased antagonist of G protein signaling but not β-arrestin–mediated internalization of CXCR4. Similar properties were shared by a nonpeptide, small-molecule inhibitor that also did not stimulate tolerance. These results suggest that the use of biased GPCR antagonists could be of therapeutic benefit in patients who have developed tolerance to nonbiased antagonists.

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