Abstract 3728: Targeting MCL-1 expression, through the inhibition of CDK9 and super enhancer driven transcription, offers multiple opportunities for rational drug combinations
Authors: Wontak Kim, Katherine K. Soh, Ye Sol Lee, Peter Peterson, Clifford J. Whatcott, Adam Siddiqui-Jain, Steven Weitman, David J. Bearss, Steven L. Warner
Journal: Cancer Research (2016)

Abstract Downregulating the expression and function of MCL-1 through the inhibition of cyclin-dependent kinase-9 (CDK9) has proven to be a valuable strategy to target this important pro-survival signal in malignant cells of numerous cancer types. This is exemplified by the ability of alvocidib, a potent CDK9 inhibitor, to inhibit the expression of MCL-1 at both the transcript and protein levels in multiple cell lines from both hematological and solid tumor origins. The timing and duration of MCL-1 knockdown varies between cell type; however, the knockdown is consistent and in some cell lines persistent after the removal of drug. Although alvocidib has demonstrated single agent activity in both the clinic and in nonclinical models, strategies that exploit MCL-1-dependent drug resistance, are allowing for the more rational use of alvocidib in combination with standard-of-care and investigational agents. Here, we demonstrate that treatment with alvocidib, followed by treatment with cytarabine and mitoxantrone (regimen called FLAM), is synergistic in nonclinical models of acute myeloid leukemia (AML). The FLAM regimen results in a significant increase in apoptosis in comparison to any of the single agents alone. This synergy correlates with the downregulation of MCL-1 expression by alvocidib treatment, which places the cancer cells into a heightened state to undergo apoptosis when induced by cytarabine and mitoxantrone treatments. Additionally, the FLAM regimen has demonstrated robust clinical activity in both front-line and relapsed/refractory AML patients. The knockdown of MCL-1 by alvocidib can also be exploited when used in combination with 5-azacytidine (5-aza). BCL-2 family members, including MCL-1 have been described as mechanisms of resistance to 5-aza. Treatment of cells with alvocidib, to repress MCL-1 expression prior to 5-aza treatment, reduced the 5-aza cell viability EC50 more than 2.5-fold, from 1.8 μM to 0.6 μM in MV4-11 cells. The alvocidib/5-aza combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. MCL-1 dependence is a known mechanism of resistance to BCL-2-targeting agents, such as venetoclax (ABT-199). Alvocidib is an effective approach to targeting MCL-1 leading to the sensitization of cancer cells to venetoclax. Finally, the rational drug combinations described here are further supported by the finding that MCL-1-dependence, measured by NOXA priming, correlates with clinical benefit from treatment with an alvocidib-containing regimen (eg. FLAM) in AML patients. In conclusion, MCL-1 is a key downstream target of inhibiting CDK-9 with alvocidib. Combination strategies using alvocidib have emerged as a powerful solution for overcoming MCL-1 dependent drug resistance. Citation Format: Wontak Kim, Katherine K. Soh, Ye Sol Lee, Peter Peterson, Clifford J. Whatcott, Adam Siddiqui-Jain, Steven Weitman, David J. Bearss, Steven L. Warner. Targeting MCL-1 expression, through the inhibition of CDK9 and super enhancer driven transcription, offers multiple opportunities for rational drug combinations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3728.