Journal
BRITISH JOURNAL OF CANCER
Volume 118, Issue 3, Pages 388-397Publisher
SPRINGERNATURE
DOI: 10.1038/bjc.2017.432
Keywords
CDK9 inhibitor; ABT-199; flavopiridol; MCL-1; BCL-2; myeloma
Categories
Funding
- National Institutes of Health [P50 CA142509-01, CA100866, UH2TR001373, CA167708]
- NIH-NCI Cancer Center Core Grant [5P30CA016059-29]
- NIH-NCI Cancer Center Support Grant [P30 CA016059]
- NATIONAL CANCER INSTITUTE [P50CA142509, R01CA205607, R01CA100866, R01CA167708, P30CA016059] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UH2TR001373] Funding Source: NIH RePORTER
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Background: The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets. Methods: Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo. Results: FP synergistically increased ABT-199 lethality in both ABT-199-sensitive and insensitive MM cells. FP blocked CDK9 activation/positive transcription elongation factor B phosphorylation, downregulated MCL-1, increased BCL-2/MCL-1 ratios, and upregulated BIM. MCL-1 ectopic expression or knockdown in MM cells significantly diminished or increased ABT-199 sensitivity, respectively. CDK9 knockdown triggered MCL-1 downregulation and increased ABT-199 activity, whereas BIM knockdown significantly reduced FP/ABT-199 lethality. FP also enhanced ABT-199 lethality in unfavourable prognosis primary MM cells. HS-5 cell co-culture failed to protect MM cells from the FP/ABT-199 regimen, suggesting circumvention of microenvironmental signals. Finally, FP/ABT-199 significantly increased survival in systemic xenograft and immune-competent MM models while exhibiting minimal toxicity. Conclusions: These findings argue that CDK9 inhibitors, for example, FP may increase the antimyeloma activity of ABT-199, including in unfavourable-risk MM minimally responsive to ABT-199 alone.
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