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.

Targeting Survival Cascades Induced by Activation of Raf/Raf/MEK/ERK and PI3K/Akt Pathways to Sensitize Cancer Cells to Therapy / McCubrey JA; Franklin RA; Bertrand FE; Taylor JR; Chappell WH; Midgett ML; Wong EWT; Abrams SL; Stadelman KM; Misaghian N; Ludwig DE; Basecke J; Libra M; Stivala F; Milella M; Tafuri A; Martelli AM; Terrian DM; Lehmann BD; Steelman LS.. - STAMPA. - (2008), pp. 81-115.

Targeting Survival Cascades Induced by Activation of Raf/Raf/MEK/ERK and PI3K/Akt Pathways to Sensitize Cancer Cells to Therapy

MARTELLI, ALBERTO MARIA;
2008

Abstract

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.
2008
Sensitization of Resistant Cancer Cells to Cytotoxic Therapy
81
115
Targeting Survival Cascades Induced by Activation of Raf/Raf/MEK/ERK and PI3K/Akt Pathways to Sensitize Cancer Cells to Therapy / McCubrey JA; Franklin RA; Bertrand FE; Taylor JR; Chappell WH; Midgett ML; Wong EWT; Abrams SL; Stadelman KM; Misaghian N; Ludwig DE; Basecke J; Libra M; Stivala F; Milella M; Tafuri A; Martelli AM; Terrian DM; Lehmann BD; Steelman LS.. - STAMPA. - (2008), pp. 81-115.
McCubrey JA; Franklin RA; Bertrand FE; Taylor JR; Chappell WH; Midgett ML; Wong EWT; Abrams SL; Stadelman KM; Misaghian N; Ludwig DE; Basecke J; Libra M; Stivala F; Milella M; Tafuri A; Martelli AM; Terrian DM; Lehmann BD; Steelman LS.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/67204
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