Page 167 - Haematologica Vol. 110 - January 2025

ARTICLE - Targeted CDK7 and BRD4 inhibition in myeloma Y. Yao et al.
Figure 3. JQ1 and YKL-5-124 combination treatment induces transcriptomic alterations in multiple myeloma cells. (A) AMO1 cells were treated with 200 nM JQ1 and 50 nM YKL-5-124 for 24 hours individually and in combination and then subjected to RNA-se- quencing analysis. The Venn diagram shows overlap of genes in these three groups (log2 fold change >1, adjusted P<0.05 or log2 fold change <-1, adjusted P<0.05). (B) Canonical pathway analysis was done using ingenuity pathway analysis (IPA). Top predicted negative canonical pathways are shown in the bubble plot. (C) Biological upstream regulators associated with CDK7 and BET in- hibition were identified using IPA. Top predicted upstream regulators for RNA-sequencing data in the group treated with the YKL- 5-124 and JQ1 combination are shown in the table (red = activated, green = inhibited). (D) SKMM1 and XG1 cells were treated with 100 nM JQ1 and 100 nM YKL-5-124 for 24 hours individually and in combination, and western blot analysis was performed using antibodies against MYC and tubulin. (E) MYBL2 log2 fold change following treatment with single agents or the combination regimen compared to the dimethyl sulfoxide control. Log2FC: log2 fold change, COMB: combination.
preclinical models.11,13 However, despite being a promising target in preclinical models with known c-MYC dependency, monotherapy trials assessing the efficacy and safety profile of BET inhibitors in MM fell short of expectations. In the OTX015 clinical trial, activity was not noted in any of the 12 MM patients, with only two (17%) experiencing stable
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disease.13 Moreover, BET inhibitors demonstrated a relatively high incidence of treatment-emergent adverse events, with thrombocytopenia, nausea, diarrhea, and fatigue ranking as the top four adverse events of all grades.14
One of the main challenges of monotherapy is the potential for cancer cells to develop resistance over time. Cancer cells,
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