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

ABSTRACT

Introduction: 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.

KEYWORDS:

• Acute myeloid leukemia (AML)
• mTORC1/2 dual inhibitor
• leukemia stem cells
• PI3K/AKT/mTOR pathway
• self-renewal
• tumor microenvironment

Article highlights

• Controlling mTOR activity is critical for the pathological regulation of malignant hematopoiesis.

• The complexity of multiple regulatory mechanisms, including cross-talk from compensatory oncogenic pathways and feedback loops leading to rebound activation of PI3K and other tyrosine kinases following the mTOR inhibition, underlies the inadequacy of the single pharmacological inhibition of PI3K/AKT/mTOR signaling.

• Combination of allosteric mTOR inhibitors with standard chemotherapy or targeted agents has a greater anti-leukemia efficacy.

• Dual mTORC1/2 inhibitors, and dual PI3K/mTOR inhibitors show greater activity through blocking multiple mechanisms of signaling circuits in pre-clinical AML models.

• Detailed comparison of targets in the self-renewal mechanisms and metabolism of HSCs and LSCs, which may associate with mTOR signaling, should provide valuable insights for overcoming the current limitations of leukemia therapy.

• The ongoing rapid advances in genomics, proteomics and metabolomics assays will build the platforms for success in novel therapeutic combinatorial approaches incorporating mTORC1 inhibition to eradicate AML.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.