Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo

J Invest Dermatol. 2011 Feb;131(2):495-503. doi: 10.1038/jid.2010.327. Epub 2010 Nov 4.

Abstract

The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Furans / pharmacology
  • Humans
  • In Vitro Techniques
  • Mechanistic Target of Rapamycin Complex 1
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Melanoma / physiopathology
  • Mice
  • Mice, Nude
  • Multiprotein Complexes
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Skin Neoplasms / physiopathology
  • TOR Serine-Threonine Kinases
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / metabolism
  • Transcription Factors
  • Transplantation, Heterologous

Substances

  • Antibiotics, Antineoplastic
  • Crtc2 protein, mouse
  • Enzyme Inhibitors
  • Furans
  • Multiprotein Complexes
  • PI103
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteins
  • Pyridines
  • Pyrimidines
  • Trans-Activators
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus