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CCR1 inhibition sensitizes multiple myeloma cells to glucocorticoid therapy

Bert Luyckx1, Maaike Van Trimpont2, Fien Declerck3

  • 1VIB-UGent Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, Gent 9052, Belgium; Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Gent 9000, Belgium; Cancer Research Institute Ghent (CRIG), Corneel Heymanslaan 10, Gent 9000, Belgium.

Pharmacological Research
|March 25, 2025
PubMed

Insights

This study reveals that blocking the chemokine receptor CCR1 enhances glucocorticoid (GC) effectiveness in multiple myeloma (MM). Targeting CCR1 may overcome GC resistance in MM patients.

Area of Science:

  • Hematology
  • Immunology
  • Pharmacology

Background:

  • Glucocorticoids (GC) are essential for multiple myeloma (MM) treatment.
  • MM cells develop resistance to GC-induced apoptosis by utilizing the bone marrow microenvironment.
  • Mechanisms underlying GC resistance in MM are not fully understood.

Purpose of the Study:

  • To investigate the role of chemokine receptor CCR1 and its ligand CCL3 in GC resistance in MM.
  • To evaluate the therapeutic potential of blocking CCR1 signaling in combination with GC treatment for MM.

Main Methods:

  • Utilized MM cell lines, primary patient samples, and a xenograft mouse model.
  • Administered dexamethasone (GC) alone and in combination with CCR1 antagonist BX471.
  • Assessed apoptosis, protein expression (pro- and antiapoptotic, lysosomal), and CCR1 mRNA/protein levels.

Main Results:

  • Blocking CCR1 signaling with BX471 significantly enhanced dexamethasone's anti-MM effects.
  • The combination therapy shifted the apoptotic balance towards cell death and affected lysosomal proteins.
  • GC-induced CCR1 downregulation was impaired in a GC-resistance model, and CCR1 inhibition partially reversed resistance.

Conclusions:

  • CCR1 signaling contributes to GC resistance in multiple myeloma.
  • Inhibiting CCR1 represents a promising strategy to resensitize MM cells to glucocorticoid therapy.
  • This approach offers a potential new avenue for improving MM treatment outcomes.
Keywords:
Chemokine receptorGlucocorticoid resistanceGlucocorticoidsMultiple myeloma

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