Drug Target for Cancer: mTOR

Drug Targets for Cancer: mTOR and Cancer

mTOR signaling plays a key role in cell growth, protein translation, autophagy, and metabolism. Activation of mTOR contributes to the pathogenesis of many cancer types. Upstream, phosphatidylinositol 3 -kinase (PI3K)/Akt signaling is deregulated through a variety of mechanisms, including overexpression or activation of growth factor receptors such as human epidermal growth factor receptor 2 (HER-2) and insulin-like growth factor receptor (IGFR), mutations in PI3K and mutations/amplifications of Akt. Tumor suppressor phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is a negative regulator of PI3K signaling. PTEN expression is decreased in many cancers, including breast, endometrial, thyroid, and prostate cancers; melanoma; and glioblastoma. PTEN may be downregulated through several mechanisms, including mutations, loss of heterozygosity, methylation, aberrant expression of regulatory microRNA, and protein instability. Activated mTOR signaling is also associated with tumor-predisposition syndromes: Cowden's syndrome (PTEN mutations), Peutz-Jeghers syndrome (LKB1 mutations), tuberous sclerosis (TSC1/2 mutations), and neurofibromatosis (NF1 mutations). Thus mTOR signaling is activated in conditions of proliferative dysregulation and in many cancer types. Activation of mTOR results in phosphorylation of its effectors, the best studied of which are eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1). 4E-BP1 hyperphosphorylation leads to inhibition of 4E-BP binding to eukaryotic initiation factor 4E (eIF4E), activating translation. eIF4E is rate-limiting for capdependent translation. The translational efficiency of mRNA with highly complex 5 untranslated regions is especially dependent on eIF4E. eIF4E enhances cell proliferation, survival, and angiogenesis by leading to selective translation of mRNA such as cyclin D1, Bcl-2, Bcl-xL and vascular endothelial growth factor (VEGF) as well as the nucleocytoplasmic transport of selected mRNA such as cyclin D1. S6K1 is a key regulator of cell growth. It phosphorylates ribosomal protein S6 and, in some models, enhances the translation of mRNAs possessing a 5 terminal oligopyrimidine tract. S6K1 also phosphorylates other important targets, including insulin receptor substrate 1 (IRS-1), eukaryotic initiation factor 4B, programmed cell death 4, eukaryotic elongation factor-2 kinase, mTOR, glycogen synthase kinase 3, and S6K1 Aly/REF-like target. Both eIF4E and S6K1 are implicated in cellular transformation, and their overexpression has been linked to poor cancer prognosis. Rapamycin and its analogs bind FK506 binding protein, and this complex binds to mTOR, inhibiting downstream signaling. Rapamycin causes cell cycle arrest in a broad spectrum of cancer types. In addition to direct antitumor effects, rapamycin also inhibits endothelial cell proliferation, hypoxia inducible factor 1 and VEGF expression, angiogenesis, and vascular permeability. Taken together, these data demonstrate the importance of mTOR signaling in cancer and support a role for mTOR as an antitumor target.

Drug Targets for Cancer: mTOR related Products

Other vital drug targets for cancer like mTOR:

Drug Targets for Cancer: mTOR Related Reference

Easton J B, Houghton P J. mTOR and cancer therapy[J]. Oncogene, 2006, 25(48): 6436-6446.
Meric-Bernstam F, Gonzalez-Angulo A M. Targeting the mTOR signaling network for cancer therapy[J]. Journal of Clinical Oncology, 2009, 27(13): 2278-2287.

Drug Targets for Cancer: mTOR Related Information