Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: How mutations can result in therapy resistance and how to overcome resistance

James A. McCubrey, Linda S. Steelman, William H. Chappell, Stephen L. Abrams, Richard A. Franklin, Giuseppe Montalto, Melchiorre Cervello, Massimo Libra, Saverio Candido, Grazia Malaponte, Maria C. Mazzarino, Paolo Fagone, Ferdinando Nicoletti, Jörg Bäsecke, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Michele Milella, Agostino Tafuri, Francesca Chiarini, Camilla EvangelistiLucio Cocco, Alberto M. Martelli

Research output: Contribution to journalArticlepeer-review

Abstract

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending onthe presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

Original languageEnglish
Pages (from-to)1068-1111
Number of pages44
JournalOncotarget
Volume3
Issue number10
Publication statusPublished - 2012

Keywords

  • Akt
  • Cancer stem cells
  • mTOR
  • PI3K
  • Raf
  • Targeted therapy
  • Therapy resistance

ASJC Scopus subject areas

  • Oncology

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