CCR1 inhibition sensitizes multiple myeloma cells to glucocorticoid therapy

Le résumé fourni par la source

Glucocorticoids (GC) are cornerstone drugs in the treatment of multiple myeloma (MM). Because MM cells exploit the bone marrow microenvironment to obtain growth and survival signals, resistance to glucocorticoid-induced apoptosis emerges, yet the underlying mechanisms remain poorly characterized. Here, we identify that the chemokine receptor CCR1, together with its main ligand CCL3, plays a pivotal role in reducing the glucocorticoid sensitivity of MM cells. We show that blocking CCR1 signaling with the antagonist BX471 enhances the anti-MM effects of the glucocorticoid dexamethasone in MM cell lines, primary patient material and a myeloma xenograft mouse model. Mechanistically, the drug combination shifts the balance between pro- and antiapoptotic proteins towards apoptosis and deregulates lysosomal proteins. Our findings suggest that CCR1 may play a role in glucocorticoid resistance, as the GC-induced downregulation of CCR1 mRNA and protein is blunted in a GC-resistance onset model. Moreover, we demonstrate that inhibiting CCR1 partially reverses this resistance, providing a promising strategy for resensitizing MM cells to GC treatment. • Elevated CCR1 expression is associated with worse prognosis in multiple myeloma patients upon progression. • Inhibition of CCR1 signaling enhances glucocorticoid sensitivity of (primary) multiple myeloma cells. • Partial glucocorticoid resistance in myeloma cells is accompanied by a loss of CCR1 downregulation. • Blocking CCR1 signaling can reverse partial glucocorticoid resistance in multiple myeloma cells.

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