mTOR, a new therapeutic target in acute myeloid leukemia.
The mTOR (mammalian target of rapamycin) serine threonine kinase is involved in the regulation of the cell cycle, apoptosis and angiogenesis. mTOR inhibitors (rapamycin, or analogues such as CCI-779, RAD001, AP23573), which have been shown to have a potent anti-neoplastic effect in many solid tumor models, are now being used in clinical trials. Recent data have shown that the mTOR pathway is also aberrantly activated in hematological malignancies including acute myeloid leukemia (AML). This disease still has a bad prognosis and new therapeutic strategies are required. Rapamycin, used at low concentrations, induces the profound inhibition of AML cell clonogenic properties in 60% of cases while sparing their normal counterparts. Moreover, clinical responses have been achieved in poor-risk AML patients. In this review, we discuss the possible mechanisms of mTOR activation, the mechanisms involved in the inhibition of cell proliferation by rapamycin, the possible resistance mechanisms and ways of improving rapamycin efficacy in the context of AML.
Récher
Christian
C
Département d'Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Institut National de la Santé et de la Recherche Médicale (Inserm) U563, CPTP, Toulouse, France. recher.c@chu-toulouse.fr
Dos Santos
Cédric
C
Demur
Cécile
C
Payrastre
Bernard
B
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases