Figure 3.

Targeting the PI3K/Akt/mTOR pathway in AML. The PI3K/Akt/mTOR pathway is commonly dysregulated in AML caused by mutations in membrane-bound proteins such as receptor tyrosine kinases (RTKs) and small GTPase Ras. Activating mutations in fms-like tyrosine kinase 3 (FLT3), such as the FLT3-internal tandem duplication (FLT3-ITD), are an important mechanism leading to dysregulation of PI3K/Akt/mTOR signaling. The ITD mutation causes ligand-independent activation of the FLT3 receptor, leading to constitutive activation of the PI3K/Akt/mTOR pathway. Numerous small-molecule inhibitors of this pathway include FLT3 inhibitors (FLT3i), dual PI3K/mTORi, allosteric mTORi, pan-class I and isoform-specific PI3Ki, ATP-competitive and allosteric Akti, and ATP-competitive mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibitors (mTORC1i and mTORC2i). The red arrow indicates elevated Akt phosphorylation, whereas the red blunt-ended lines represent negative regulation (inhibition). IRS-1 = insulin receptor substrate 1, PIP₂ = phosphatidylinositol-4,5-phosphate, PIP₃ = phosphatidylinositol-3,4,5-phosphate, PTEN = phosphatase and tensin homolog, PDK1 = phosphoinositide-dependent kinase-1, TSC 1/2 = tuberous sclerosis complex 1/2, ATP = adenosine triphosphate, GDP = guanosine diphosphate, GTP = guanosine triphosphate, Rheb = Ras homolog enriched in brain, 4E-BP1 = eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1, S6K1 = ribosomal protein S6 kinase beta-1, rpS6 = ribosomal protein S6. The black blunt-ended lines indicate the main targets for therapeutic intervention. Created with BioRender.com.