Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML. Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival. Although abnormalities of mTOR signaling are strongly associated with neoplastic leukemic proliferation, the role of pharmacologic inhibitors of mTOR in the treatment of AML has not been established. Expert opinion: Inhibition of mTOR signaling has in general modest growth-inhibitory effects in preclinical AML models and clinical trials. Yet, combination of allosteric mTOR inhibitors with standard chemotherapy or targeted agents has a greater anti-leukemia efficacy. In turn, dual mTORC1/2 inhibitors, and dual PI3K/mTOR inhibitors show greater activity in pre-clinical AML models. Further, understanding the role of mTOR signaling in stemness of leukemias is important because AML stem cells may become chemoresistant by displaying aberrant signaling molecules, modifying epigenetic mechanisms, and altering the components of the bone marrow microenvironment.

Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia / Tabe, Yoko; Tafuri, Agostino; Sekihara, Kazumasa; Yang, Haeun; Konopleva, Marina. - In: EXPERT OPINION ON THERAPEUTIC TARGETS. - ISSN 1472-8222. - STAMPA. - 21:7(2017), pp. 705-714. [10.1080/14728222.2017.1333600]

Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia

TAFURI, Agostino;
2017

Abstract

Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML. Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival. Although abnormalities of mTOR signaling are strongly associated with neoplastic leukemic proliferation, the role of pharmacologic inhibitors of mTOR in the treatment of AML has not been established. Expert opinion: Inhibition of mTOR signaling has in general modest growth-inhibitory effects in preclinical AML models and clinical trials. Yet, combination of allosteric mTOR inhibitors with standard chemotherapy or targeted agents has a greater anti-leukemia efficacy. In turn, dual mTORC1/2 inhibitors, and dual PI3K/mTOR inhibitors show greater activity in pre-clinical AML models. Further, understanding the role of mTOR signaling in stemness of leukemias is important because AML stem cells may become chemoresistant by displaying aberrant signaling molecules, modifying epigenetic mechanisms, and altering the components of the bone marrow microenvironment.
2017
acute myeloid leukemia (aml); pi3k/akt/mtor pathway; leukemia stem cells; mtorc1/2 dual inhibitor; self-renewal; tumor microenvironment
01 Pubblicazione su rivista::01a Articolo in rivista
01 Pubblicazione su rivista::01g Articolo di rassegna (Review)
Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia / Tabe, Yoko; Tafuri, Agostino; Sekihara, Kazumasa; Yang, Haeun; Konopleva, Marina. - In: EXPERT OPINION ON THERAPEUTIC TARGETS. - ISSN 1472-8222. - STAMPA. - 21:7(2017), pp. 705-714. [10.1080/14728222.2017.1333600]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/970022
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