TY - JOUR
T1 - Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors
T2 - How mutations can result in therapy resistance and how to overcome resistance
AU - McCubrey, James A.
AU - Steelman, Linda S.
AU - Chappell, William H.
AU - Abrams, Stephen L.
AU - Franklin, Richard A.
AU - Montalto, Giuseppe
AU - Cervello, Melchiorre
AU - Libra, Massimo
AU - Candido, Saverio
AU - Malaponte, Grazia
AU - Mazzarino, Maria C.
AU - Fagone, Paolo
AU - Nicoletti, Ferdinando
AU - Bäsecke, Jörg
AU - Mijatovic, Sanja
AU - Maksimovic-Ivanic, Danijela
AU - Milella, Michele
AU - Tafuri, Agostino
AU - Chiarini, Francesca
AU - Evangelisti, Camilla
AU - Cocco, Lucio
AU - Martelli, Alberto M.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Akt
KW - Cancer stem cells
KW - mTOR
KW - PI3K
KW - Raf
KW - Targeted therapy
KW - Therapy resistance
UR - http://www.scopus.com/inward/record.url?scp=84871491627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871491627&partnerID=8YFLogxK
M3 - Article
C2 - 23085539
AN - SCOPUS:84871491627
VL - 3
SP - 1068
EP - 1111
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 10
ER -