Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mtor cascades which alter therapy response

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

Research output: Contribution to journalArticlepeer-review


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). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

Original languageEnglish
Pages (from-to)954-987
Number of pages34
Issue number9
Publication statusPublished - Sep 2012


  • Akt
  • Mtor
  • Mutations
  • Pi3k
  • Raf
  • Targeted therapy
  • Therapy resistance

ASJC Scopus subject areas

  • Oncology


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