Accession Number : AD1042321


Title :   Overcoming Resistance to Inhibitors of the Akt Protein Kinase by Modulation of the Pim Kinase Pathway


Descriptive Note : Technical Report,30 Sep 2012,14 Oct 2016


Corporate Author : University of Arizona Tucson United States


Personal Author(s) : Kraft, Andrew


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1042321.pdf


Report Date : 01 Jan 2017


Pagination or Media Count : 21


Abstract : 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 AKT/PI3K 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.


Descriptors :   prostate cancer , inhibitors , therapeutics , kinases , proteins , receptor sites(physiology) , molecules


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE