Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

被引：208

作者：

McCubrey, J. A. ^{[1
]}

Steelman, L. S. ^{[1
]}

Abrams, S. L. ^{[1
]}

Bertrand, F. E. ^{[1
]}

Ludwig, D. E. ^{[2
]}

Baesecke, J. ^{[3
]}

Libra, M. ^{[4
]}

Stivala, F. ^{[4
]}

Milella, M. ^{[5
]}

Tafuri, A. ^{[6
]}

Lunghi, P. ^{[7
]}

Bonati, A. ^{[7
,8
]}

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

机构：

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

[2] ImClone Syst, New York, NY USA

[3] Univ Gottingen, Div Hematol & Oncol, Dept Med, Gottingen, Germany

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

[5] Regina Elena Canc Ctr, Rome, Italy

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

[7] Univ Parma, Dept Clin Sci, I-43100 Parma, Italy

[8] Univ Hosp Parma, Unit Hematol & Bone Marrow Transplantat, Parma, Italy

[9] Univ Bologna, Dept Human Anat Sci, Bologna, Italy

[10] IGM CNR, IOR, Bologna, Italy

来源：

LEUKEMIA | 2008年 / 22卷 / 04期

关键词：

MEK; PI3K; Akt; signal transduction; inhibitors; chemotherapeutic drugs;

D O I：

10.1038/leu.2008.27

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.

引用

页码：708 / 722

页数：15

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