Rapamycins: Mechanism of action and cellular resistance

Shile Huang, Mary Ann Bjornsti, Peter J. Houghton

Research output: Contribution to journalReview article

267 Scopus citations

Abstract

Rapamycins are macrocyclic lactones that possess immunosuppressive, antifungal and antitumor properties. The parent compound, rapamycin, is approved as an immunosuppressive agent for preventing rejection in patients receiving organ transplantation. Two analogues, CCI-779 and RAD001 are currently being investigated as anticancer agents. Rapamycins first bind a cyclophilin FKBP12, and this complex binds and inhibits the function of mTOR (mammalian target of rapamycin) a serine/threonine (Ser/Thr) kinase with homology to phosphatidylinositol 3′ kinase. Currently, as mTOR is the only identified target, this places rapamycins in a unique position of being the most selective kinase inhibitor known. Consequently these agents have been powerful tools in elucidating the role of mTOR in cellular growth, proliferation, survival and tumorigenesis. Increasing evidence suggests that mTOR acts as a central controller sensing cellular environment (nutritional status or mitogenic stimulation) and regulating translation initiation through the eukaryotic initiation factor 4E, and ribosomal p70 S6 kinase pathways. Here we review the conserved TOR signaling pathways, conceptual basis for tumor selectivity, and the mechanisms of resistance to this class of antitumor agent.

Original languageEnglish (US)
Pages (from-to)222-232
Number of pages11
JournalCancer Biology and Therapy
Volume2
Issue number3
DOIs
StatePublished - May 1 2003
Externally publishedYes

Keywords

  • Cancer
  • Rapamycins
  • Resistance
  • Ribosomal biogenesis
  • Therapy
  • Translation initiation
  • Yeast

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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