Mammalian Target of Rapamycin Inhibition As Therapy for Hematologic Malignancies

Amit Panwalkar, Srdan Verstovsek, Francis J. Giles*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

192 Scopus citations

Abstract

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 eukarycrtic initiation factor 4E-binding protein 1, its inhibitors cause G1-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 G1-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.

Original languageEnglish (US)
Pages (from-to)657-666
Number of pages10
JournalCancer
Volume100
Issue number4
DOIs
StatePublished - Feb 15 2004

Keywords

  • AP23573
  • CCI-779
  • Mammalian target of rapamycin
  • Phosphatase and tensin homologue tumor suppressor
  • Phosphatidylinositol 3′ kinase
  • Protein kinase B
  • RAD001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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