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Proteolysis targeting chimeric molecules in MM
Levels of CRBN mRNA as a potential biomarker
of sensitivity of multiple myeloma cells to inhibition by ARV 825
CRBN expression tends to be higher in hematologic malignancies, including MM, compared to solid tumors (Figure 2A). Levels of CRBN mRNA expression across dif- ferent MM cell lines positively correlated with sensitivity of the MM cells to ARV 825 (Figure 2B, left). Isogenic
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lenalidomide resistant cells (MM1S res and KMS11 res cells) had reduced CRBN levels and were more resistant to ARV 825 compared to their parental cells (Figure 2B, right). Over-expressed or silenced CRBN in both KMS11 and KMS28BM MM cells correlated with ability of ARV 825 to either enhance (Figure 2C) or to decrease (Figure 2D) the inhibition of cell growth, respectively.
Figure 5. Combination Index (CI) plot of ARV 825 with small molecule inhibitors. Synergistic growth inhibi- tion (MTT assay) of KMS11 and KMS28BM multiple myeloma cells in the presence of ARV 825 and a small molecule inhibitor. CI defines interac- tion between ARV 825 and small mol- ecule inhibitor as plotted against a fraction of cell viability. CI<1, CI=1, and CI>1 represent synergism, addi- tive, and antagonism of the two com- pounds, respectively. Values of CI analysis are shown in Online Supplementary Table S3.
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