Abstract C202: CDK9 inhibition synergizes with BRD4 inhibitor-mediated super enhancer transcriptional repression in multiple preclinical tumor models

Abstract

Abstract The group of transcriptional regulatory proteins known collectively as the super enhancer complex (SEC) coordinate the expression of entire genetic programs directing cell fate. The SEC is also important in driving cancer progression mediated by transcription of key oncogenes such as c-Myc and Bcl-2. The SEC requires the interaction and coordination of many proteins, including cyclin-dependent kinases (CDK), bromodomain proteins (BRD), histone deacetylases (HDAC), and histone methyltransferases (HMT). Each of these proteins are the focus of significant development efforts for the treatment of cancer. SEC-regulated transcription requires recruitment of CDK9/cyclin T1 from the 7SK RNA/Hexim1 inhibitory complex by BRD4 to transcriptional start sites. CDK9 then phosphorylates RNA polymerase II, releasing it from the start site leading to productive 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 in cancer cells. 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 hematologic malignancies. However, we have found that CDK9 inhibitors, combined with bromodomain inhibitors, produced a synergistic effect by inhibiting the SEC more effectively than either of these compounds alone. Cell viability studies with various combinations resulted in an increase in potency. This was observed with alvocidib combined with JQ-1 (BRD4 inhibitor) in A549 lung cancer cells. Furthermore, the combination of alvocidib with JQ-1 completely abrogated SEC function, as measured by c-Myc or Mcl-1 expression through RT-qPCR. Similar results were achieved with other combinations of CDK9 and BRD4 inhibitors. These data, primarily focused on alvocidib and JQ-1, suggest a strong rationale for combining CDK9 and BRD4 inhibitors as a treatment strategy for multiple tumor types, including lung cancer. Furthermore, these findings may be more broadly applied to additional therapeutic targets in the SEC. These strategies yield synergistic effects at inhibiting SEC function and are highly active in tumor growth studies of cancer, in vivo. Clinical studies utilizing these combination strategies will explore this therapeutic approach. Citation Format: Ye Sol Lee, Wontak Kim, Katherine K. Soh, Peter Peterson, Clifford J. Whatcott, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner. CDK9 inhibition synergizes with BRD4 inhibitor-mediated super enhancer transcriptional repression in multiple preclinical tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C202.