IMiD/CELMoD resistance in myeloma is associated with changes in lipid metabolism that may be targetable

However, a major barrier to improving patient outcomes is the inevitable development of resistance to these agents. To explore the mechanisms underlying IMiD/CELMoD resistance, and identify novel targets for treatment, human cell line models of acquired IMiD/CELMoD resistance were generated.

Quantitative proteome analysis of these models identified common changes in lipid synthesis proteins and glucose labelling experiments confirmed altered lipid flux. Proteomic analysis of paired patient samples, from diagnosis and relapse on IMiD, suggested similar changes in lipid pathways. A genome wide CRISPR screen performed in a human multiple myeloma cell line with acquired CELMoD resistance identified dependencies in the lipid pathway genes Stearoyl-CoA Desaturase (SCD) and Membrane Bound Transcription Factor Peptidase Site 1 (MBTPS1).