Abstract B272: The novel PIM kinase inhibitor SGI-1776 significantly enhances the preclinical activity of sunitinib in renal cell carcinoma

Abstract

Abstract The PIM kinases (PIM1, PIM2, and PIM3) are constitutively active serine/threonine kinases that promote tumorigenesis in mouse models and are associated with drug resistance. Upregulation of PIM kinase expression has been reported in many malignancies including renal cell carcinoma (RCC), suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. SGI-1776 is a novel orally available small molecule inhibitor of PIM kinase activity that is currently in Phase I clinical trials. We hypothesized that inhibition of PIM kinase activity would reduce the viability of RCC cells and enhance the activity of the multi-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib. Cell viability and apoptosis assays demonstrated that SGI-1776 possessed significant in vitro activity in a panel of RCC cell lines. One of the mechanisms by which the PIM kinases have been reported to inhibit apoptosis is by phosphorylating the BH3-only protein Bad to abrogate its pro-apoptotic function. Accordingly, SGI-1776-mediated apoptosis was associated with decreased levels of the phosphorylated form of Bad. Moreover, targeted knockdown of Bad expression significantly decreased sensitivity to SGI-1776 indicating that Bad is an important mediator of the anticancer activity of this agent. Treatment with SGI-1776 also led to a markedly decrease in phosphorylated and total c-Myc levels and enhanced the activity of sunitinib in RCC cells. The addition of sunitinib to SGI-1776 further reduced c-Myc expression. Silencing of the gene suggested that c-Myc plays a significant role in sensitivity to the SGI-1776/sunitinib combination. To further evaluate this drug combination, Caki-1 and 786-O RCC xenografts were established in nude mice and they were treated orally with SGI-1776, sunitinib, or the combination. The SGI-1776/sunitinib combination significantly reduced tumor burden in both xenograft models compared to single agent therapy and was very well tolerated. Analysis of the tumors revealed that the drug combination strongly decreased tumor proliferation and induced apoptosis as measured by PCNA and TUNEL immunohistochemistry, respectively. These data indicate that PIM kinase signaling has a significant role in the biology of RCC and warrants further investigation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B272.