Abstract B178: Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9

Abstract

Of the more than 240,000 estimated new cases of breast cancer in 2016 (US), triple-negative breast cancer (TNBC) was expected to comprise roughly 12%. So named because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, TNBCs pose a unique therapeutic challenge, with only chemotherapeutic options currently available. New therapeutic options are desperately needed for patients with TNBC. Recent reports have identified a cellular addiction of TNBCs to PIM1, suggesting that the addiction is mediated by PIM regulation of Myc and BH3 proteins MCL-1 or BCL-2. The PIM family of serine/threonine kinases are highly conserved and the link between PIM and Myc function has been well studied. The second-generation PIM inhibitor, TP-3654, has been shown to suppress Myc expression in vitro. Additionally, CDK9 inhibitors are also known to suppress Myc expression. CDK9 inhibition mediates specific reductions in transcription of short-lived mRNAs such as Myc and MCL-1. The CDK9/cyclin T complex is a critical component of the P-TEFb complex, promoting productive RNA elongation through phosphorylation of serine 2 of the heptapeptide repeats of the C-terminal domain of RNA Polymerase II (RNAPII-CTD). We are developing a potent CDK9 inhibitor, alvocidib, and an oral prodrug form of alvocidib named TP-1287, and are investigating the potential clinical utility of CDK9 inhibition in acute myeloid leukemia (AML). We hypothesized that PIM and CDK9 inhibition would be an active combination in models of TNBC due to the added effect of targeting Myc through two independent mechanisms. In the TNBC cell line, MDA-MB-231, TP-3654 reduced relative Myc protein expression by 74%, while alvocidib reduced expression by 71%. The combination of TP-3654 and alvocidib reduced detectable expression 100%, as measured by standard immunoblotting, at concentrations of 100 nM with a 3-hour treatment. To test this hypothesis in vivo, TP-3654 and TP-1287 were tested in the MDA-MB-231 xenograft. Single-agent TP-3654 (150 mg/kg) reduced tumor growth (%TGI) 40.7%, while TP-1287 (3.75 mg/kg) reduced tumor growth 11.6%. The combined-treatment regimen reduced tumor growth by 58.3% at day 18 of treatment. These results support a rationale for further clinical investigation of PIM and CDK9 inhibitors for the suppression of Myc in patients with TNBC. Citation Format: Hillary Haws, Wontak Kim, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner, Clifford J. Whatcott. Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B178.