Vertical inhibition of the PI3K/Akt/mTOR pathway is synergistic in breast cancer

S. U. Woo, T. Sangai, A. Akcakanat, H. Chen, C. Wei, F. Meric-Bernstam

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Deregulation and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin (mTOR) pathway have a major role in proliferation and cell survival in breast cancer. However, as single agents, mTOR inhibitors have had modest antitumor efficacy. In this study, we evaluated the effects of vertical inhibition of mTOR and Akt in breast cancer cell lines and xenografts. We assessed the effects of mTOR inhibitor rapamycin and Akt inhibitor MK-2206, given as single drugs or in combination, on cell signaling, cell proliferation and apoptosis in a panel of cancer cell lines in vitro. The antitumor efficacy was tested in vivo. We demonstrated that MK-2206 inhibited Akt phosphorylation, cell proliferation and apoptosis in a dose-dependent manner in breast cancer cell lines. Rapamycin inhibited S6 phosphorylation and cell proliferation, and resulted in lower levels of apoptosis induction. Furthermore, the combination treatment inhibited phosphorylation of Akt and S6, synergistically inhibited proliferation and induced apoptosis with a higher efficacy. In vivo combination inhibited tumor growth more than either agent alone. Our data suggest that a combination of Akt and mTOR inhibitors have greater antitumor activity in breast cancer cells, which may be a viable approach to treat patients.

Original languageEnglish (US)
Pages (from-to)e385
JournalOncogenesis
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Vertical inhibition of the PI3K/Akt/mTOR pathway is synergistic in breast cancer'. Together they form a unique fingerprint.

Cite this