Fig. 7

Combined treatment of CDK9 and HSP90 inhibitors shows synergistic potent anti-MCL activity. A-B AZD4573 in combination with zelavespib or tanespimycin synergistically suppressed cell viability (A) and induced apoptosis (B) in Z138 cells upon treatment for 72 h. CI = (I_d1 + I_d2)/I_(d1+d2). CI, combination index; I_d1, the percentage of viability inhibition or apoptosis induction by drug #1 treatment; I_d2, the percentage of viability inhibition or apoptosis induction by drug #2 treatment; I_(d1+d2), the percentage of viability inhibition or apoptosis induction by combination treatment of drug #1 and #2. The combination effect is considered synergistic if CI < 0.9. C Western blot shows HSP90 inhibitors zelavespib and tanespimycin in combination with CDK9 inhibitor AZD4573 induced marked reduction of MYC expression and cleavage of PARP and caspase 3. D Volcano plot shows the log2 fold change (x-axis) and -log10 adjusted p-value (y-axis) of enriched pathways in different treatments. Left: at 5 nM plus zelavespib at 0.2 µM. Right: AZD4573 at 5 nM plus tanespimycin at 0.5 µM. Each dot represents an enriched pathway and is colored by significance (up: yellow, down: blue, not significant: grey). E Dot plot shows significantly enriched hallmark pathways (y-axis) for each group (x-axis) compared to control (DMSO). Dot shape represent regulation direction (circle: down, triangle: up). F Heatmaps display expression of genes from relevant pathways (rows) across conditions (columns). Data was normalized to the vehicle (DMSO) condition. Blue and yellow reflect low and high expression, respectively. Dual targeting of HSP90 and CDK9 markedly suppressed MYC_TARGETS_v1 (left), MYC_TARGETS_v2 (middle), and NF-κB targets (right). G Boxplots show representative genes altered upon treatment with CDK9 inhibitor AZD4573 and HSP90 inhibitors, alone or in combination. ^**, p < 0.01; ^***, p < 0.001; ^****, p < 0.0001