Commentary: Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor.

Abstract

The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase belonging to the phosphatidylinositol kinase-related protein kinases family, which plays a central role in regulation of cellular metabolism, growth, and proliferation (Figure ​(Figure1A)1A) (Wullschleger et al., 2006; Laplante and Sabatini, 2012). The PI3K-AKT-mTOR signaling axis is also one of the most commonly activated pathways in human cancers (Vivanco and Sawyers, 2002; Zoncu et al., 2011). A growing body of evidence identifies activation of mTOR signaling as a common occurrence in human cancers (Menon and Manning, 2008). Recently, activating mutations of mTOR itself have been identified through mining of human cancer genome databases (Hardt et al., 2011). Hyper-activation of mTOR signaling makes it an attractive target for therapeutic intervention and has driven the development of a number of mTOR inhibitors, many of which have progressed to clinical trials (Chiang and Abraham, 2007).