Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia

Abstract

The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110delta isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).

Figure 1.

The PI3K/AKT signaling pathway. An activated tyrosine kinase receptor (RTK) recruits adaptators such as Gab2 or IRS family proteins, which bind to the regulatory p85 subunit of PI3K. The latter activates the catalytic p110alpha, beta and delta subunits of PI3K. Activated PI3K complex transforms PI(4,5)P2 into PI(3,4,5)P3. The latter recruits PDK1 and AKT to the plasma membrane where AKT is phosphorylated by PDK1 on Thr308. PDK2, which is mTORC2, phosphorylates AKT on Ser473. Fully activated AKT modulates several substrates important for cell survival, cell cycle and cell growth.

Figure 2.

Regulation of mTORC1 activation downstream of AKT and interactions between mTORC1 and PI3K. Active AKT inhibits TSC2 activity through direct phosphorylation. TSC2 functions in association with the putative TSC1 to inactivate the small G protein Rheb. AKT–driven TSC1/TSC2 inactivation allows Rheb to accumulate in a GTP-bound state. Rheb-GTP activates mTORC1 by inhibiting FKBP38. mTORC1 phosphorylates p70S6 kinase which has a role in mRNA translation and which mediates a negative feedback to AKT through IRS-1 degradation. MTORC2 complex phosphorylates AKT on Ser473.