Pim-1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

The contract supports studies to define the role of the PIM1 kinase in acquired resistance to chemotherapy by prostate cancer cells. Data to date for specific aim 1 define a signaling pathway induced by docetaxel involving sequential steps of STAT3 phosphorylation expression of PIM1 and activation of NFkB signaling. Blockade of this pathway prevents drug-induced upregulation of NFkB activity and sensitizes cells to docetaxel. Other studies specific aim 2focus on identifying a mechanism through which PIM1 activates NFkB. We have unambiguously identified S937 as the major PIM1 phosphorylation site on the NFKB1p105 precursor protein through use of LCMMSMS analysis. We have now shown that phosphorylation at S937 potentiates NFkB transcriptional activity. Additional data specific aim 3 have been published to describe a small molecule inhibitor of PIM1. This molecule can sensitize prostate cancer cells to the cytotoxic effects of docetaxel in an additive or synergistic manner. Pharmacophore analysis has identified future modifications of the inhibitor.