PI3K pathway inhibitors: Better not left alone

Ben Markman, Jessica J. Tao, Maurizio Scaltriti

Research output: Contribution to journalReview article

Abstract

The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also central to many aspects of the malignant process. Genetic phenomena that lead to constitutive pathway activation are common in human cancer; the most relevant are mutations affecting the catalytic subunit of PI3K and loss of function of the PTEN tumor suppressor. These factors have made this important cascade attractive as a potential target for cancer therapeutics. A host of inhibitors are now in various stages of development that target key nodes within the PI3K pathway. To date, however, the efficacy of these agents has fallen short of expectation, with at least one possible explanation being the presence of feedback loops and cross-talk that exists within and between PI3K and other signaling pathways. Accordingly, enthusiasm is again high as strategies employing therapeutic combinations are gaining pace, with encouraging results documented in both preclinical studies and emerging clinical trials. Here, we review the agents that have reached evaluation in early phase clinical studies of human subjects with cancer, and discuss the rationale for and use of novel drug combinations.

Original languageEnglish (US)
Pages (from-to)895-906
Number of pages12
JournalCurrent pharmaceutical design
Volume19
Issue number5
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Keywords

  • Akt
  • Clinical trial
  • PI3K
  • PI3K inhibitor
  • PIK3CA
  • PTEN
  • Therapeutic combination
  • mTOR

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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