TARGETING MTOR SUBSTRATES IN TREATING PROLIFERATIVE DISEASES

摘要

Some aspects of this invention relate to the identification of over 300 mTOR kinase targets by a comprehensive phosphoproteomics assay. Some aspects of this invention relate to targeting mTOR kinase targets, for example, Grb10, FOXK1, ZEB2, NDRG3, LARP1, SRPK2, CDK12, MIB1, or IBTK, in treating hyperproliferative disease. Some aspects of this invention relate to methods to determine the level of mTOR activity by measuring the level of phosphorylation of an mTOR targeted phosphorylation site, for example, a Grb10, FOXK1, ZEB2, NDRG3, LARP1, SRPK2, CDK12, MIB1, and/or IBTK phosphorylation site. Some aspects of this invention relate to methods for distinguishing different classes of mTOR activity in a cell based on phosphoproteomic analysis of mTOR-targeted proteins. Some aspects of this invention relate to the classification of a hyperproliferative disease based on phosphoproteomic analysis of mTOR-targeted proteins. Some aspects of this invention relate to the personalization of therapeutic methods for the treatment of hyperproliferative disease based on phosphoproteomics. Some aspects relate to therapeutic methods including administering to a subject an mTOR inhibitor, an mTOR inhibitor and an additional kinase inhibitor, or a dual inhibitor of mTOR and an additional kinase based on the phosphorylation levels of mTOR targets determined in the subject. Some aspects of this invention relate to the discovery that Grb10 is an mTOR-targeted tumor suppressor gene.