Abstract 2835: Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition

Abstract

Abstract Triple negative breast cancer (TNBC) is a highly heterogeneous disease, notoriously challenging to treat with standard chemotherapy options, and therefore is an area of intense focus for discovery of novel effective combination therapies. Here we used a previously described technology platform called CIVO, which enables assessment of multiple drugs and drug combinations simultaneously in living tumors, to identify drug combinations that result in synergistic anti-tumor activity in the HCC1187 model of TNBC. Our study focused on agents that combine with Voruciclib, a novel clinical stage oral CDK inhibitor with potent activity (<100 nM) against CDKs 1, 4, and 9. Among the drug combinations investigated, robust localized anti-tumor activity as measured by cleaved caspase 3 (CC3) positive apoptotic cells, was observed upon combined tumor exposure to Voruciclib and the proteasome inhibitor Bortezomib. In contrast, exposure to either Voruciclib or Bortezomib as single agents showed little anti-tumor activity. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies where tumor regression was induced by the Voruciclib/Bortezomib combination, but no significant impact on tumor progression was observed in xenografted subjects treated with either single agent. The ability of TNBC cells to withstand stressors such as chemotherapy may be due in part to activation of adaptive survival pathways including the unfolded protein (UPR) and endoplasmic reticulum (ER) stress responses. As observed in previous reports, exposure of HCC1187 cells to Bortezomib alone led to an increase in two markers of the cytoprotective arm of the UPR/ER stress pathway: XBP-1s and GRP-78/BIP. Consistent with the possibility that Voruciclib impedes the cytoprotective UPR/ER stress response induced by Bortezomib, exposure to the drug combination substantially reduced protein expression of both XBP-1s and GRP-78 with concomitant induction of cPARP. Voruciclib also neutralized upregulation of these same proteins by the classic ER stress inducing agent Tunicamycin. These studies provide a foundation for further investigation of breast cancer relevant anti-cancer agents that induce UPR/ER stress responses in combination with Voruciclib for treating TNBC patients. Citation Format: Joyoti Dey, Joseph Casalini, Sally Ditzler, Matt Biery, Angela Merrell, Derek Thirstrup, Marc Grenley, Richard Klinghoffer. Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition. [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 2835.