Pharmacological Effects of GSK2656157, a Novel PERK Kinase Inhibitor, on Tumor Growth and Angiogenesis Using DCE-MRI in Pancreatic Tumor Model

Hasan Alsaid¹, Charity Atkins², Sarah Lee³, Tinamarie Skedzielewski¹, Mary V. Rambo¹, Shu-Yun Zhang², David J. Figueroa², Brandon Whitcher³, Rakesh Kumar², Beat M. Jucker¹

The eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK is one of three mediators of the unfolded protein response signal transduction pathway. GSK2656157 is the first-in-class, small molecule inhibitor of PERK enzyme activity in cells with an IC50 in the range of 10-30 nM as reflected by inhibition of stress-induced PERK autophosphorylation. In this study, we investigated the pharmacological effect of GSK2656157 on tumor growth and angiogenesis using dynamic contrast enhanced MRI (DCE-MRI) in the BxPc3 xenograft tumor model. The results suggest DCE-MRI can be used as a PD marker to monitor the antiangiogenic effect of a PERK inhibition in human subjects.