FIGURE 1 | Signalling of the PI3K/AKT/mTOR pathway and relevant drugs that target each of the components of the pathway.

From the following article:

Development of PI3K inhibitors: lessons learned from early clinical trials

Jordi Rodon, Rodrigo Dienstmann, Violeta Serra & Josep Tabernero

Nature Reviews Clinical Oncology 10, 143-153 (March 2013)


Development of PI3K inhibitors: lessons learned from early clinical trials

The heterodimer of the PI3Ks (p110 and p85) generates the lipid messenger PIP3, which mediates activation of several protein kinases, including AKT. AKT stimulates glycolysis by activating glycolytic enzymes (via GSK3β) and by regulating glucose transporters.40 This important molecular mechanism drives tumour cells to avidly consume glucose as a source of ATP, also known as the Warburg effect.108 AKT also promotes survival through BAD and transcription of the antiapoptotic genes, BIM and FASLG via FoxO. AKT also promotes cell-cycle progression by regulating the cyclin-dependent kinase inhibitors CDKN1A and CDKN1B (also known as p21 and p27) through activation of cyclin D1 and cyclin E1, and the transcription factors JUN and MYC. Protein synthesis, cell growth and proliferation, and metabolic functions downstream of AKT are regulated by the mTORC1/S6K axis and downstream effectors, such as 4EBP1.47 Autocrine and paracrine angiogenesis is driven by mTORC1/HIF1α/VEGF expression. Importantly, negative regulation of this pathway is conferred by PTEN and inositol polyphosphate-4-phosphatase type II, a protein encoded by INPP4B, which cleave a phosphate group in PIP3 or PIP2, respectively.109 Numerous compounds have been developed to inhibit different nodes in the PI3K/AKT/mTOR signalling pathway. These include PI3K inhibitors (that based on their selectivity can be subdivided into dual pan-PI3K–mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors), mTOR inhibitors (that can be divided into allosteric inhibitors [rapalogues] and mTOR catalytic inhibitors) and AKT inhibitors (including both allosteric inhibitors and catalytic inhibitors). Abbreviations: 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; BAD, BCL2 antagonist of cell death; CDKN1, cyclin-dependent kinase inhibitor 1; FASLG, Fas antigen ligand; FoxO, forkhead box O; GFR, growth factor receptor; GSK3, glycogen synthase kinase-3; HIF1, hypoxia-inducible factor 1; INPP4B, type II inositol 3,4-bisphosphate 4-phosphatase; mTORC, mTOR complex; PDK1, 3-phosphoinositide-dependent protein kinase 1; PIP2, phosphatidylinositol (4,5)-biphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PRAS40, proline-rich AKT1 substrate 1; PTEN, phosphatase and tensin homologue; RPS6, 40S ribosomal protein S6; RSK, 90 kDa ribosomal protein S6 kinase.

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