Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells

J Invest Dermatol. 2008 Aug;128(8):2013-23. doi: 10.1038/jid.2008.44. Epub 2008 Mar 6.

Abstract

The RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are activated through multiple mechanisms and appear to play a major role in melanoma progression. Herein, we examined whether targeting the RAS-RAF-MEK-ERK pathway with the RAF inhibitor sorafenib and/or the PI3K-AKT-mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma. A combination of sorafenib (4 microM) with rapamycin (10 nM) potentiated growth inhibition in all six metastatic melanoma cell lines tested. The absolute enhancement of growth inhibition rates ranged from 13.0-27.8% in different cell lines (P<0.05, combination treatment vs monotreatment). Similar results were obtained with combinations of the MEK inhibitors U0126 (30 microM) or PD98059 (50 microM) with rapamycin (10 nM). The combined treatment of melanoma cells with sorafenib and rapamycin led to an approximately twofold increase of cell death compared with sorafenib monotreatment (P<0.05) as assessed by propidium iodide staining and cell death detection ELISA. Moreover, sorafenib in combination with rapamycin completely suppressed invasive melanoma growth in organotypic culture mimicking the physiological context. These effects were associated with complete downregulation of the antiapoptotic proteins Bcl-2 and Mcl-1. Sorafenib combined with rapamycin appears to be a promising strategy for the effective treatment of melanoma and merits clinical investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Apoptosis* / drug effects
  • Benzenesulfonates / pharmacology
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Chromones / pharmacology
  • Down-Regulation / drug effects
  • Flavonoids / pharmacology
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Melanoma / drug therapy
  • Melanoma / pathology*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / drug effects
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Morpholines / pharmacology
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Invasiveness
  • Niacinamide / analogs & derivatives
  • Nitriles / pharmacology
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyridines / pharmacology
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / pathology*
  • Sorafenib
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Wortmannin

Substances

  • Androstadienes
  • Benzenesulfonates
  • Butadienes
  • Chromones
  • Flavonoids
  • Morpholines
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitriles
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • Transcription Factors
  • U 0126
  • Niacinamide
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Sorafenib
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mitogen-Activated Protein Kinase Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Sirolimus
  • Wortmannin