Impact of cancer-associated mutations in CC chemokine receptor 2 on receptor function and antagonism
L S den Hollander1, O J M Béquignon1, X Wang1
1Leiden Academic Centre for Drug Research, Division of Drug Discovery and Safety, Leiden, The Netherlands.
Abstract:
CC chemokine receptor 2 (CCR2), a G protein-coupled receptor, plays a role in many cancer-related processes such as metastasis formation and immunosuppression. Since ∼ 20 % of human cancers contain mutations in G protein-coupled receptors, ten cancer-associated CCR2 mutants obtained from the Genome Data Commons were investigated for their effect on receptor functionality and antagonist binding. Mutations were selected based on either their vicinity to CCR2's orthosteric or allosteric binding sites or their presence in conserved amino acid motifs. One of the mutant receptors, namely S101P2.63 with a mutation near the orthosteric binding site, did not express on the cell surface. All other studied mutants showed a decrease in or a lack of G protein activation in response to the main endogenous CCR2 ligand CCL2, but no change in potency was observed. Furthermore, INCB3344 and LUF7482 were chosen as representative orthosteric and allosteric antagonists, respectively. No change in potency was observed in a functional assay, but mutations located at F1163.28 impacted orthosteric antagonist binding significantly, while allosteric antagonist binding was abolished for L134Q3.46 and D137N3.49 mutants. As CC chemokine receptor 2 is an attractive drug target in cancer, the negative effect of these mutations on receptor functionality and drugability should be considered in the drug discovery process.
Insights
Cancer-associated mutations in CC chemokine receptor 2 (CCR2) can impair its function and antagonist binding. These findings are crucial for developing effective cancer therapies targeting CCR2 signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- CC chemokine receptor 2 (CCR2) is a G protein-coupled receptor implicated in cancer progression, including metastasis and immunosuppression.
- Approximately 20% of human cancers harbor mutations in G protein-coupled receptors, highlighting the clinical relevance of studying receptor variants.
Purpose of the Study:
- To investigate the functional impact of ten cancer-associated CC chemokine receptor 2 (CCR2) mutants on receptor activity and antagonist interactions.
- To assess how specific CCR2 mutations affect G protein activation, ligand binding, and the efficacy of orthosteric and allosteric antagonists.
Main Methods:
- Ten cancer-associated CCR2 mutants were generated and analyzed for cell surface expression.
- Functional assays were performed to evaluate G protein activation by CCL2 and the potency of orthosteric (INCB3344) and allosteric (LUF7482) antagonists.
- Antagonist binding affinities were assessed for specific mutants to determine the impact on drug interaction.
Main Results:
- One mutant (S101P) failed to express on the cell surface.
- Most mutants exhibited reduced or absent G protein activation by CCL2, without altering potency.
- Mutations at F116 significantly affected orthosteric antagonist binding, while mutations at L134Q and D137N abolished allosteric antagonist binding.
Conclusions:
- Cancer-associated CCR2 mutations can negatively impact receptor function, including G protein signaling and antagonist binding.
- These findings underscore the importance of considering CCR2 mutations in cancer drug discovery to ensure therapeutic efficacy and target engagement.
- Understanding the effects of CCR2 variants is critical for the rational design of targeted cancer therapies.
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