In BALL and other hematological malignancies, cellintrinsic oncogenic lesions and cellextrinsic microenvironmental cues converge on a set of intracellular signaling pathways that drive proliferation and survival . The improvement of compounds that inhibit prosurvival signaling proteins has potential to enhance patient outcomes and enhance the efficacy of current treatments. The target of rapamycin can be a essential signaling enzyme whose activity is elevated in most leukemia cells . mTOR is a serine/ threonine kinase that exists in two multiprotein complexes, mTORC1 and mTORC2, with various upstream activators and downstream substrates . Rapamycin and its analogs act via an allosteric mechanism and don’t completely inhibit the function of mTORC1 or mTORC2 . Rapalogs have cytostatic activity in countless cell contexts but aren’t strongly cytotoxic, and display restricted activity in leukemia models and clinical trials.
A novel class of ATPcompetitive mTOR inhibitors, here termed mTOR kinase inhibitors , totally inhibit each mTOR complexes and have improved cytotoxic activity and antileukemic efficacy in preclinical testing . mTOR functions in a complicated, nonlinear network of kinases that involve phosphoinositide 3kinase and AKT more helpful hints . Activation of PI3K and AKT promotes diverse elements of cell growth, proliferation, survival and metabolism . Complete AKT activation calls for phosphorylation on Thr308 by phosphoinositidedependent kinase1 and on Ser473 by mTORC2. Activated AKT can phosphorylate tuberous sclerosis complex2 and PRAS40 to promote mTORC1 activity, yet AKT activity will not be expected for mTORC1 function in some cell contexts. Thus, leukemia cells lacking PI3K/AKT activity can survive by keeping residual mTORC1 activity by way of other mechanisms .
By way of phosphorylation of S6 kinases and eukaryotic initiation aspect 4E binding proteins , mTORC1 promotes biosynthesis of proteins and teicoplanin lipids expected for cell growth and division. Even so, mTORC1 also initiates negative feedback mechanisms that attenuate the activity of each PI3K and AKT. Rapalogs suppress some of these feedback loops, leading to elevated PI3K/AKT signaling that might possibly promote leukemia cell survival. The complexity in the PI3K/AKT/mTOR network provides rationale for targeting multiple elements with the pathway to achieve maximum anticancer efficacy . Pharmacological data have supported this notion. A lot on the evidence comes from research of ATPcompetitive, panselective inhibitors targeting both PI3K and mTOR. These panPI3K/mTOR inhibitors have impressive anticancer activity in a wide range of tumor models .
More proof has emerged from studies of mTOR kinase inhibitors, which are selective for the mTOR enzyme in comparison with PI3K . Like panPI3K/ mTOR inhibitors, mTOR kinase inhibitors fully block both mTORC1 and mTORC2 and commonly avoid the acute PI3K/AKT rebound impact of rapalogs.