Modeling of glucocorticoid resistance in multiple myeloma reveals mechanisms and markers of glucocorticoid resistance.

Multiple Myeloma (MM) is a malignancy characterized by an uncontrolled proliferation of malignant plasma cells in the bone marrow and remains incurable. Treatment typically consists of a multimodal approach, with glucocorticoids (GC) as a crucial treatment pillar in the diagnosis and relapsed settings. Inevitably, patients become therapy resistant, but to which component of the treatment armamentarium the tumor becomes refractory is unknown. Here we used different in cellulo models of GC resistance to gain insights into the mechanistic processes of emerging GC therapy resistance. We found that differential baseline GC responsiveness of the cells is associated with significant differences in the timing and the degree to which myeloma cell lines become resistant to GCs. We corroborated that the chemokine receptor CCR1 is a shared biomarker between MM cell lines upon the emergence of GC resistance. Significant overlap exists between pathways enriched in partial GC-resistant MM.1S cells and those enriched in relapsed patients whose treatment included GCs. In addition, enrichment analyses demonstrated that alterations in metabolism and plasma cell expression signatures are associated with decreased sensitivity to GCs. From these analyses, we validated a biomarker, fatty acid synthase (FASN), and pinpointed its pivotal role in determining the GC sensitivity of myeloma cells, offering future opportunities for enforcement of GC sensitivity and re-sensitization.