Overcoming Resistance to Inhibitors of the Akt Protein Kinase by Modulation of the Pim Kinase Pathway
Technical Report,30 Sep 2012,14 Oct 2016
University of Arizona Tucson United States
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Small molecules targeted at specific signal transduction pathways hold great promise for creating a new approach to prostate cancer treatment. In this proposal, the applicant research team demonstrates that resistance to small molecule AKT protein kinase inhibitors is mediated by the ability of the Pim protein kinases to in part stimulate increases in receptortyrosine kinases RTKs. In particular the Pim protein kinases are shown to induce resistance to c-Met inhibition. The c-Mettyrosine kinase is an activator of AKT. Results demonstrate that Pim can phosphorylate eIF4B and control IRES mediated translation of these RTKs. Additional experiments show that inhibition of AKTPI3K kills through the induction of ROS, andthe Pim protein kinase through the induction of Nrf2 blocks the action of these agents. Animal experiments demonstrate that a combination of Pim and AKT inhibitor decreases the growth of subcutaneous grafts of human prostate cancer. The knowledge gained through these studies will be essential to the development of combined chemotherapeutic strategies totreat prostate cancer.
- Medicine and Medical Research