New developments in mammalian target of rapamycin inhibitors for the treatment of sarcoma.
Bottom Line: The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase in the phosphatidylinositol 3-kinase/serine/threonine protein kinase Akt signaling pathway, has an important role in the regulation of protein synthesis, cell proliferation, angiogenesis, and metabolism.Alterations of the mTOR signaling pathway are common in malignancies, including several types of sarcoma.Rapamycin and its analogs (rapalogs) are effective anticancer agents in a broad range of preclinical models.
Affiliation: Division of Medical Hematology/Oncology, Northwestern University, Chicago, Illinois, USA. email@example.comShow MeSH
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Mentions: Mammalian target of rapamycin is a member of the PI3K-kinase related kinase superfamily.11, 12 Human mTOR exists in 2 different multiprotein complexes: mTOR complex 1 (mTORC1), consisting of mTOR, mTOR complex subunit LST8 (mLST8), and regulatory-associated protein of mTOR (raptor); and mTOR complex 2 (mTORC2), composed of mTOR, mLST8, rapamycin-insensitive companion of mTOR (rictor), and mammalian stress-activated protein kinase-interacting protein 1 (mSin1).12 Of the 2 complexes, mTORC1 has been studied more extensively and reportedly regulates most mTOR effects on protein synthesis and gene expression associated with cell growth, metabolism, cell proliferation, angiogenesis, and cell survival. The role of mTORC2 is less understood, but reports suggest that mTORC2 phosphorylates Akt in the PI3K/Akt pathway and regulates the organization of the cytoskeleton (Fig. .1).6-8, 13, 14 The activity of mTOR is regulated by growth factors and their receptors, which transmit signals through the PI3K/Akt and Ras pathways.9 Members of the EGFR family (eg, EGFR, human epidermal growth factor 2), IGF, and VEGF receptors stimulate mTOR activity through the small guanosine triphosphatase (GTPase) Ras homolog enriched in brain.9 Signals generated by these receptors are regulated by PTEN, which inhibits PI3K signaling; neurofibromatosis type-1 (NF1), a tumor suppressor that reduces Ras activity; and tuberous sclerosis complex (TSC1) and TSC2, which form a complex to block the activation of mTOR.11 The activity of mTOR also is regulated by cellular stress—when intracellular adenosine triphosphate (ATP) levels are depleted, the adenosine monophosphate-activated protein kinase is activated through the tumor suppressor LKB1 (serine threonine kinase 11). Adenosine monophosphate-activated protein kinase subsequently activates another tumor suppressor, TSC1/TSC2, thereby leading to mTOR inactivation.10, 14
Affiliation: Division of Medical Hematology/Oncology, Northwestern University, Chicago, Illinois, USA. firstname.lastname@example.org