Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response.

被引：229

作者：

McCubrey, James A. ^{[1
]}

Steelman, Linda S. ^{[1
]}

Chappell, William H. ^{[1
]}

Abrams, Stephen L. ^{[1
]}

Montalto, Giuseppe ^{[2
]}

Cervello, Melchiorre ^{[3
]}

Nicoletti, Ferdinando ^{[4
]}

Fagone, Paolo ^{[4
]}

Malaponte, Grazia ^{[4
]}

Mazzarino, Maria C. ^{[4
]}

Candido, Saverio ^{[4
]}

Libra, Massimo ^{[4
]}

Baesecke, Joerg ^{[5
]}

Mijatovic, Sanja ^{[6
]}

Maksimovic-Ivanic, Danijela ^{[6
]}

Milella, Michele ^{[7
]}

Tafuri, Agostino ^{[8
]}

Cocco, Lucio ^{[9
]}

Evangelisti, Camilla ^{[10
]}

Chiarini, Francesca ^{[10
]}

Martelli, Alberto M. ^{[9
,10
]}

机构：

[1] E Carolina Univ, Dept Microbiol & Immunol, Brody Sch Med, Greenville, NC 27858 USA

[2] Univ Palermo, Dept Internal Med & Specialties, Palermo, Italy

[3] Ist Biomed & Immunol Mol Alberto Monroy, Consiglio Nazl Ric, Palermo, Italy

[4] Univ Catania, Dept Biomed Sci, Catania, Italy

[5] Univ Gottingen, Dept Med, Gottingen, Germany

[6] Univ Belgrade, Dept Immunol, Inst Biol Res Sinisa Stankov, Belgrade, Serbia

[7] Regina Elena Inst Canc Res, Rome, Italy

[8] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Rome, Italy

[9] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy

[10] Rizzoli Orthoped Inst, Inst Mol Genet, Natl Res Council, Bologna, Italy

来源：

ONCOTARGET | 2012年 / 3卷 / 09期

关键词：

Targeted Therapy; Therapy Resistance; Mutations; Raf; Akt; PI3K; mTOR; NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; ACUTE MYELOID-LEUKEMIA; EXTENDS LIFE-SPAN; GROWTH-FACTOR-I; CELL-CYCLE ARREST; EPITHELIAL-MESENCHYMAL TRANSITION; CANCER-ASSOCIATED FIBROBLASTS; SUPPRESSOR GENE PTEN/MMAC1; PLECKSTRIN HOMOLOGY DOMAIN;

D O I：

10.18632/oncotarget.652

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：954 / 987

页数：34

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