Characterizing Acquired Proteasome Inhibitor Resistance in Human Multiple Myeloma Cell Lines

Proteasome inhibitors (PIs) are a mainstay treatment for multiple myeloma (MM). Unfortunately, cure is rare. Here, we attempted to define mechanisms for PI resistance. Two PIresistant MM cell lines were serendipitously developed by blasticidin exposure. These cells had unfolded protein response profiles resembling their PI-sensitive parental cell lines. PI resistance was demonstrated to be due to Mycoplasma infection, which impeded drug inhibition of the proteasome target. Screening of patient samples however did not reveal mycoplasma infection in primary MM cells. Instead, gene expression analyses of primary MM suggested that epigenetic dysregulation (revealed by cancer testis antigen expression) correlates with clinical bortezomib resistance. We therefore screened small molecule epigenetic probes to identify regulators of PI response. While most had no effect on PI response, MM inhibition and bortezomib sensitization was observed with the pan-BET inhibition, JQ1, suggesting that additional evaluation of PIs in combination with BET (or BRD4) inhibitors is warranted.M.Sc