Journal
ONCOTARGET
Volume 3, Issue 9, Pages 954-987Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.652
Keywords
Targeted Therapy; Therapy Resistance; Mutations; Raf; Akt; PI3K; mTOR
Categories
Funding
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (Ministry for Education, Universities and Research) - MIUR [n. RBNE08YYBM]
- CNR from Italian Ministry of Economy and Finance for the Project FaReBio di Qualita
- MIUR [RBAP10447J-003, RBAP11ZJFA_001]
- Italian Ministry of Health, Ricerca Finalizzata Stemness
- Health, Ricerca Finalizzata Stemness
- MinSan
- Italian Association for Cancer Research (AIRC)
- Cariplo Foundation
- Sapienza, University of Rome
- Italian Ministry of Health
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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). 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.
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