Journal
ONCOTARGET
Volume 3, Issue 10, Pages 1068-1111Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.659
Keywords
Targeted Therapy; Therapy Resistance; Cancer Stem Cells; Raf; Akt; PI3K; mTOR
Categories
Funding
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (Ministry for Education, Universities and Research) - MIUR [2008THTNLC, RBAP10447J-003, RBAP11ZJFA_001]
- FIRB-MERIT [RBNE08YYBM]
- Italian Ministry of Economy and Finance
- Italian Ministry of Health, Ricerca Finalizzata Stemness
- Italian Association for Cancer Research (AIRC)
- Cariplo Foundation
- Italian Ministry of Health
- Sapienza, University of Rome [2009-11]
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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 on the 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.
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