Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

Abstract

The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.

Figure 1

(a) mTORC1 protein composition; (b) mTORC1 upstream activators; (c) mTORC1 downstream targets; (d) mTORC1 cellular functions. Legend: DEPTOR: DEP domain TOR-binding protein; mTOR: mechanistic target of rapamycin; RAPTOR: regulatory-associated protein of mTOR; PRAS40: proline-rich AKT substrate 40 kDa; mLST8: mammalian lethal with Sec-13 protein 8; PI3K: phosphatidylinositol-3-kinase; PIP2: phosphatidylinositol (4,5)-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; PTEN: phosphatase and tensin homolog; AKT: protein kinase B; TSC1/2: tuberous sclerosis complex 1/2; GTP: guanosine triphosphate; RHEB: RAS homolog enriched in brain; FKBP12: 12-kDa intracellular FK506-binding protein; rapalogs: rapamycin analogs; 4EBP1: eukaryotic initiation factor 4E (eIF4E)-binding protein; S6K: ribosomal S6 kinases; GRB10: growth factor receptor-bound protein 10; ULK1/Atg13/FIP200: unc-51-like kinase 1/mammalian autophagy-related gene 13/focal adhesion kinase family-interacting protein of 200 kDa; ATF4: activating transcription factor 4; TFEB: transcription factor EB.

Figure 2

(a) mTORC2 protein composition; (b) mTORC2 upstream activators; (c) mTORC2 downstream targets; (d) mTORC2 cellular functions. Legend: mTOR: mechanistic target of rapamycin; RICTOR: rapamycin-insensitive companion of mTOR; mLST8: mammalian lethal with Sec-13 protein 8; DEPTOR: DEP domain TOR-binding protein; PROTOR: protein observed with RICTOR; mSIN1: stress-activated map kinase-interacting protein 1; PI3K: phosphatidylinositol-3-kinase; PIP2: phosphatidylinositol (4,5)-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; PTEN: phosphatase and tensin homolog; AKT: protein kinase B; SGK1: serum and glucocorticoid-regulated kinase 1; PKC: protein kinase C; HDACs: histone deacetylases; PFK-1: phosphofruttokinase-1; HK2: hexokinase 2; GLUT4: glucose transporter type 4; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 3

Schematic representation showing paths and points of action of the mTOR kinase domain inhibitors (AZD8055 (AstraZeneca) and OSI-027 (OSI Pharmaceuticals)) currently evaluated in clinical trials. Legend: PI3K: phosphatidylinositol-3-kinase; PIP2: phosphatidylinositol (4,5)-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; PTEN: phosphatase and tensin homolog; AKT: protein kinase B; TSC1/2: tuberous sclerosis complex 1/2; GTP: guanosine triphosphate; RHEB: RAS homolog enriched in brain; mTOR: mechanistic target of rapamycin; RAPTOR: regulatory-associated protein of mTOR; PRAS40: proline-rich AKT substrate 40 kDa; mLST8: mammalian lethal with Sec-13 protein 8; DEPTOR: DEP domain TOR-binding protein; RICTOR: rapamycin-insensitive companion of mTOR; PROTOR: protein observed with RICTOR; mSIN1: stress-activated map kinase-interacting protein 1; FKBP12: 12-kDa intracellular FK506-binding protein; rapalogs: rapamycin analogs; FATC: FAT carboxyl terminal; FRB: FKBP-rapamycin-binding domain.