Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors' anticancer efficacy

Cancer Biol Ther. 2008 Dec;7(12):1952-8. doi: 10.4161/cbt.7.12.6944. Epub 2008 Dec 8.

Abstract

The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Several mTOR inhibitors are currently being tested in cancer clinical trials. Both PI3K/Akt and MEK/ERK signaling regulate mTOR axis. However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors' anticancer efficacy. We are interested in developing strategies for enhancing mTOR-targeted cancer therapy. In this study, we report that mTOR inhibition also induced activations of the MEK/ERK signaling pathway in some cancer cell lines after a prolonged treatment. The combination of rapamycin with the MEK inhibitor U0126 significantly enhanced growth inhibitory effects of cancer cells, suggesting that MEK/ERK activation may counteract mTOR inhibitors' anticancer efficacy. Similarly, the combination of an mTOR inhibitor with the EGF receptor inhibitor erlotinib synergistically inhibited the growth of both human cancer cells in cell cultures and xenografts in nude mice. Moreover, the presence of erlotinib suppressed rapamycin-induced phosphorylation of Akt, ERK and eIF4E as well, implying that erlotinib can suppress mTOR inhibition-induced feedback activation of several survival signaling pathways including Akt, ERK and eIF4E. Thus, we suggest a therapeutic strategy for enhancing mTOR-targeted cancer therapy by preventing mTOR inhibition-induced feedback activation of several survival mechanisms.

Publication types

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

MeSH terms

  • Antibiotics, Antineoplastic / therapeutic use
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Renal Cell / drug therapy
  • Cell Line, Tumor
  • Cell Survival
  • Enzyme Inhibitors / pharmacology
  • Erlotinib Hydrochloride
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Kidney Neoplasms / drug therapy
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinases / metabolism*
  • Protein Kinases / therapeutic use
  • Quinazolines / therapeutic use
  • Signal Transduction
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • temsirolimus
  • Erlotinib Hydrochloride
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • Sirolimus