Targeting AKT/mTOR and ERK MAPK Signaling Inhibits Hormone-Refractory Prostate Cancer in a Preclinical Mouse Model

J Clin Invest. 2008 Sep;118(9):3051-64. doi: 10.1172/JCI34764.

Abstract

The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Hormones / metabolism
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Models, Biological
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • TOR Serine-Threonine Kinases

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Hormones
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases