Development of PI3K/AKT/mTOR Pathway Inhibitors and Their Application in Personalized Therapy for Non–Small-Cell Lung Cancer Vassiliki Papadimitrakopoulou,

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Development of PI3K/AKT/mTOR Pathway Inhibitors and Their Application in Personalized Therapy for Non–Small-Cell Lung Cancer Vassiliki Papadimitrakopoulou, MD Journal of Thoracic Oncology Volume 7, Issue 8, Pages 1315-1326 (August 2012) DOI: 10.1097/JTO.0b013e31825493eb Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 The PI3K/AKT/mTOR pathway. Extrinsic binding and subsequent activation of extracellular growth factors to transmembrane receptor tyrosine kinases induce PI3K recruitment to the plasma membrane. Once there, the PI3K subunit p110 catalyzes the phosphorylation of PIP2 to PIP3. PIP3 localizes AKT to the plasma membrane, where it gets phosphorylated by 3-phosphoinositide-dependent kinase 1. After a second phosphorylation event by mTOR complex 2, the fully activated AKT dissociates from the plasma membrane and activates targets that drive increased cell growth, metabolism, survival, and proliferation. The pathway is negatively regulated by the tumor-suppressor phosphatase and tensin homolog, which dephosphorylates PIP3 to the inactive PIP2, which can then be further dephosphorylated to PIP by inositol polyphosphate-4-phosphatase, type II. Another attenuation mechanism is mediated by S6 kinase-mediated inhibition of the adaptor molecule insulin receptor substrate 1. Cross-talk between the parallel RAS/mitogen-activated protein kinase/ERK and PI3K/AKT/mTOR pathways can also take place via direct activation of PI3K by RAS. Other links to parallel pathways include mTOR complex 1 activation via ERK inhibition of tuberous sclerosis 2 and RAF inactivation by phosphorylated AKT. PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; RAS, Rat sarcoma; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; ERK, extracellular signal-regulated kinase. Journal of Thoracic Oncology 2012 7, 1315-1326DOI: (10.1097/JTO.0b013e31825493eb) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions