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Mammalian target of rapamycin inhibition as therapy for hematologic malignancies
Author(s) -
Panwalkar Amit,
Verstovsek Srdan,
Giles Francis J.
Publication year - 2004
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.20026
Subject(s) - pi3k/akt/mtor pathway , rptor , cancer research , protein kinase b , microbiology and biotechnology , pten , ribosome biogenesis , ribosomal s6 kinase , ribosomal protein s6 , biology , cyclin dependent kinase , mtorc2 , p70 s6 kinase 1 , cell cycle , signal transduction , mtorc1 , cell , biochemistry , ribosome , rna , gene
The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3‐kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal‐transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E‐binding protein 1, its inhibitors cause G 1 ‐phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G 1 ‐phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI‐779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies. Cancer 2004;100:657–66. © 2004 American Cancer Society.