CCR1 inhibition sensitizes multiple myeloma cells to glucocorticoid therapy

One of the cornerstone drugs in the treatment of multiple myeloma (MM) are glucocorticoids. Because MM cells hijack 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 glucocorticoid sensitivity of MM cells. We show that blocking of CCR1 signalling with the antagonist BX471 enhances the anti-MM effects of the glucorticoid dexamethasone in several MM cell lines, primary patient material and in a myeloma xenograft mouse model. Mechanistically, the drug combination shifts the balance between pro- and antiapoptotic proteins towards apoptosis and deregulates lysosomal proteins. We further find that the glucocorticoid-induced downregulation of CCR1 mRNA and protein is blunted in a glucocorticoid-resistance onset model. Finally, we demonstrate that CCR1 inhibition partially reverses GC-resistance, hereby offering a viable glucocorticoid resensitization strategy for MM treatment.