Will PI3K pathway inhibitors be effective as single agents in patients with cancer?

Joan T. Garrett, Anindita Chakrabarty, Carlos L. Arteaga

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis regulates essential cellular functions including cell survival, proliferation, metabolism, migration, and angiogenesis. The PI3K pathway is activated in human cancers by mutation, amplification, and deletion of genes encoding components of this pathway. The critical role of PI3K in cancer has led to the development of drugs targeting the effector mechanisms of this signaling network. Recent studies have shown that inhibition at multiple levels of the PI3K pathway results in FOXOdependent feedback reactivation of several receptor tyrosine kinases (RTKs) which, in turn, limit the sustained inhibition of this pathway and attenuates the action of therapeutic antagonists. This suggests that if used as single agents, PI3K pathway inhibitors may have limited clinical activity. We propose herein that to successfully target the output of the PI3K pathway in cancer cells, combination therapies that hinder these compensatory mechanisms should be used. Thus, combination therapies that target RTKs, PI3K, and mTOR activities may be required to maximize the clinical benefit derived from treatment with these inhibitors.

Original languageEnglish (US)
Pages (from-to)1314-1319
Number of pages6
JournalOncotarget
Volume2
Issue number12
DOIs
StatePublished - Dec 2011

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Keywords

  • Cancer
  • Combination therapy
  • Mtor
  • Oncotarget
  • PI3K
  • Receptor tyrosine kinases

ASJC Scopus subject areas

  • Oncology

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