Abstract 2698: Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia

Abstract

The super enhancer complex (SEC) is a group of transcription regulatory proteins that coordinate the expression of genetic programs which determine cell identity and drive disease states, such as cancer. In acute myeloid leukemia (AML), SECs have been shown to turn on transcriptional programs that drive tumorigenesis and disease progression. The SEC is replete with potential therapeutic targets that have been the focus of many drug development efforts; including cyclin-dependent kinases (CDK), bromodomain proteins (BRD), histone deacetylases (HDAC), and histone methyltransferases (HMT). SEC-regulated transcription begins as CDK9/cyclin T1 is recruited from an inhibitory complex by BRD4 and brought to the transcriptional start site of genes. CDK9 phosphorylates RNA polymerase II, releasing it from the SEC and leading to transcriptional elongation and gene expression. Considering the close association of CDK9 and BRD4, we hypothesized that the combination of CDK9 and BRD4 inhibitors would have synergistic effects, particularly in AML, a disease largely driven by SEC function. Alvocidib is a potent CDK9 inhibitor with validated clinical activity in AML from multiple Phase II studies in over 400 patients. Additionally, BRD4 inhibitors have demonstrated early promise in clinical studies with a focus on AML. We found that CDK9 inhibitors combined with bromodomain inhibitors produced a synergistic effect by inhibiting the SEC more effectively than either of these compounds alone. For example, cell viability studies with various combinations resulted in an increase in potency. This was observed with alvocidib combined with JQ-1 (BRD4 inhibitor) in MV4-11 AML cells. Furthermore, the combination of alvocidib with JQ-1 completely abrogated SEC function, as measured by c-myc expression through RT-qPCR. Similar results were achieved with other combinations of CDK9 and BRD4 inhibitors. The alvocidib and JQ-1 combination was also evaluated in an MV4-11 mouse xenograft model. As single agents, alvocidib (2.5 mg/kg) exhibited a 44% tumor growth inhibition and JQ-1 (25 mg/kg) a 1% growth inhibition. When these two doses were combined there was 100% tumor growth inhibition. These data, primarily focused on alvocidib and JQ-1, suggest a strong rational for combining CDK9 and BRD4 inhibitors as a treatment strategy for AML. Furthermore, these findings could be more broadly applied to additional therapeutic targets in the SEC, such as DOT1L and HDACs. These strategies yield synergistic effects at inhibiting SEC function and are highly active in tumor growth studies of AML in vivo. Clinical studies utilizing these combination strategies are the next steps to further explore this approach. Citation Format: Brigham L. Bahr, Kyle S. Maughan, Katherine K. Soh, Jeremiah J. Bearss, Wontak Kim, Peter Peterson, Clifford Whatcott, Adam Siddiqui-Jain, Steve L. Warner, David J. Bearss. Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2698. doi:10.1158/1538-7445.AM2015-2698