Targeting translation in acute myeloid leukemia: a new paradigm for therapy?
The mammalian Target Of Rapamycin Complex 1 (mTORC1) pathway is commonly activated in cancer cells including acute myeloid leukemia (AML) and has been designed as a major target for cancer therapy. However, the efficacy of rapalogs (mTORC1 inhibitors) is limited in AML, due to the feedback activation of PI3K or ERK signaling pathways upon mTORC1 inhibition, which pathways should be simultaneously targeted to enhance the anti-leukemic activity of rapalogs. Moreover, the mRNA translation process is mTORC1-independent in AML, although markedly contributing to oncogenesis in this disease, and this also strongly participates to rapalogs resistance. Translation inhibition could be achieved by directly targeting the translation initiating complex using the 4EGI-1 compound, anti-eIF4E antisense oligonucleotides or the antiviral drug ribavirin or by second generation mTOR inhibitors (TORkinhibs). These new approaches represent promising perspectives for AML therapy that should have clinical development in the future.
Tamburini
Jerome
J
Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France.
Green
Alexa S
AS
Chapuis
Nicolas
N
Bardet
Valerie
V
Lacombe
Catherine
C
Mayeux
Patrick
P
Bouscary
Didier
D
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000628:therapy*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D048049:Extracellular Signal-Regulated MAP Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D012333:RNA, Messenger; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors