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PI3K/AKT/mTOR signaling in cancer
Research Guide
What is PI3K/AKT/mTOR signaling in cancer?
PI3K/AKT/mTOR signaling in cancer is a key intracellular pathway that regulates cell growth, metabolism, and survival, frequently deregulated by mutations or aberrant activation to promote tumorigenesis and progression.
The field encompasses 46,656 works on mTOR signaling in growth control, metabolism, and disease, with central focus on the PI3K/AKT pathway, Raptor, TSC2, and rapamycin. Laplante and Sabatini (2012) in "mTOR Signaling in Growth Control and Disease" detail how mTOR integrates nutrient and growth factor signals to control cellular processes often disrupted in cancer. Saxton and Sabatini (2017) in "mTOR Signaling in Growth, Metabolism, and Disease" expand on mTOR's role in metabolic reprogramming that supports tumor proliferation.
Topic Hierarchy
Research Sub-Topics
PI3K Activation and AKT Phosphorylation in Cancer
This sub-topic details upstream activation of PI3K by receptor tyrosine kinases, PIP3 production, and AKT phosphorylation events driving cell survival and proliferation. Researchers investigate PIK3CA mutations and isoform-specific inhibitors.
mTORC1 Regulation by TSC-Rheb Axis
This sub-topic examines TSC1/2 complex as a GTPase-activating protein for Rheb, controlling mTORC1 activation in response to growth factors and nutrients. Researchers study TSC2 phosphorylation sites and loss-of-function mutations in hamartomas.
mTORC2 and AKT Feedback Loops
This sub-topic covers mTORC2-mediated phosphorylation of AKT at Ser473, its role in cytoskeletal dynamics, and feedback inhibition loops with IGF-1R/PDK1. Researchers explore Rictor knockout phenotypes and dual PI3K/mTOR inhibitors.
mTOR in Autophagy and Metabolism
This sub-topic investigates mTORC1 inhibition of ULK1-dependent autophagy initiation and its regulation of lipid, nucleotide, and amino acid metabolism. Researchers analyze nutrient-sensing via Rag GTPases and everolimus effects on glycolysis.
Rapamycin Analogs and Resistance Mechanisms
This sub-topic focuses on allosteric mTORC1 inhibitors like everolimus, clinical trials in renal cell carcinoma, and resistance via AKT reactivation or 4EBP1 mutations. Researchers develop ATP-competitive inhibitors like torin1.
Why It Matters
Deregulation of PI3K/AKT/mTOR signaling drives human cancers through enhanced cell survival and growth, as shown by Vivanco and Sawyers (2002) in "The phosphatidylinositol 3-Kinase–AKT pathway in human cancer," which links pathway hyperactivation to multiple tumor types. Sarbassov et al. (2005) in "Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex" demonstrate that Akt phosphorylation at Ser473 by the rictor-mTOR complex is critical for full activation implicated in cancer pathogenesis. Manning and Cantley (2007) in "AKT/PKB Signaling: Navigating Downstream" map downstream effectors that promote tumor metabolism and resistance to therapy. Cantley (2002) in "The Phosphoinositide 3-Kinase Pathway" highlights PI3K's production of phosphatidylinositol-3,4,5-trisphosphate, enabling signaling for cell survival in cancers.
Reading Guide
Where to Start
"mTOR Signaling in Growth Control and Disease" by Laplante and Sabatini (2012), as it provides a foundational overview of mTOR's integration of signals for growth and metabolism relevant to cancer without assuming advanced pathway knowledge.
Key Papers Explained
Laplante and Sabatini (2012) in "mTOR Signaling in Growth Control and Disease" establishes core mTOR functions, which Saxton and Sabatini (2017) in "mTOR Signaling in Growth, Metabolism, and Disease" builds upon by detailing metabolic disease links. Sarbassov et al. (2005) in "Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex" connects upstream AKT regulation to mTOR, while Manning and Cantley (2007) in "AKT/PKB Signaling: Navigating Downstream" maps effectors downstream. Vivanco and Sawyers (2002) in "The phosphatidylinositol 3-Kinase–AKT pathway in human cancer" and Cantley (2002) in "The Phosphoinositide 3-Kinase Pathway" frame the full PI3K input in oncogenic contexts.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Recent works continue to explore mTOR complex distinctions and AKT phosphorylation dynamics, as evidenced by high citations of Saxton and Sabatini (2017) and Sarbassov et al. (2005), with no new preprints or news indicating focus on therapeutic resistance mechanisms in ongoing cancer studies.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | Mutations of the BRAF gene in human cancer | 2002 | Nature | 10.5K | ✓ |
| 2 | mTOR Signaling in Growth Control and Disease | 2012 | Cell | 8.3K | ✓ |
| 3 | Cell Signaling by Receptor Tyrosine Kinases | 2010 | Cell | 7.8K | ✓ |
| 4 | mTOR Signaling in Growth, Metabolism, and Disease | 2017 | Cell | 7.1K | ✓ |
| 5 | Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR C... | 2005 | Science | 6.1K | ✕ |
| 6 | AKT/PKB Signaling: Navigating Downstream | 2007 | Cell | 6.0K | ✓ |
| 7 | The phosphatidylinositol 3-Kinase–AKT pathway in human cancer | 2002 | Nature reviews. Cancer | 6.0K | ✕ |
| 8 | Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small... | 2006 | New England Journal of... | 5.7K | ✓ |
| 9 | TOR Signaling in Growth and Metabolism | 2006 | Cell | 5.7K | ✓ |
| 10 | The Phosphoinositide 3-Kinase Pathway | 2002 | Science | 5.5K | ✕ |
Frequently Asked Questions
What is the role of mTOR in cancer signaling?
mTOR integrates signals from nutrients and growth factors to regulate cell growth and metabolism, often hyperactivated in tumors. Laplante and Sabatini (2012) in "mTOR Signaling in Growth Control and Disease" describe mTOR complexes controlling anabolic processes disrupted in disease. Saxton and Sabatini (2017) in "mTOR Signaling in Growth, Metabolism, and Disease" emphasize mTOR's control over metabolic pathways supporting cancer cell proliferation.
How is Akt regulated in the PI3K/AKT/mTOR pathway?
Akt activation requires phosphorylation at Thr308 by PDK1 and Ser473 by the rictor-mTOR complex. Sarbassov et al. (2005) in "Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex" show this dual phosphorylation is essential for Akt's role in cancer and diabetes pathogenesis. Deregulation leads to unchecked signaling promoting tumorigenesis.
What are the downstream effects of PI3K/AKT signaling?
PI3K generates phosphatidylinositol-3,4,5-trisphosphate to recruit and activate AKT, driving survival and growth signals. Manning and Cantley (2007) in "AKT/PKB Signaling: Navigating Downstream" outline effectors regulating metabolism and proliferation in cancer. Vivanco and Sawyers (2002) in "The phosphatidylinositol 3-Kinase–AKT pathway in human cancer" link this to oncogenic transformation across tumor types.
How does PI3K initiate the pathway in cancer?
PI3K phosphorylates lipids at membranes to produce signaling molecules that activate downstream components like AKT. Cantley (2002) in "The Phosphoinositide 3-Kinase Pathway" explains PI3K's catalysis of phosphatidylinositol-3,4,5-trisphosphate for cell survival signals frequently altered in cancer. This step is central to pathway deregulation in human malignancies.
What is the connection between mTOR and growth control in tumors?
mTOR signaling governs protein synthesis and autophagy to control cellular growth, often upregulated in cancer. Wullschleger et al. (2006) in "TOR Signaling in Growth and Metabolism" describe TOR's nutrient-sensing role leading to metabolic shifts in proliferating cells. Laplante and Sabatini (2012) connect this to disease states including cancer.
Open Research Questions
- ? How do specific mutations in PI3K/AKT/mTOR components confer resistance to rapamycin-based therapies in different cancer types?
- ? What are the precise mechanisms by which rictor-mTOR phosphorylates Akt Ser473 to sustain signaling in nutrient-deprived tumors?
- ? How does crosstalk between PI3K/AKT/mTOR and receptor tyrosine kinase pathways, such as BRAF, amplify oncogenic growth?
- ? In what ways does mTOR regulate metabolic reprogramming to support cancer cell survival under therapeutic stress?
- ? Which downstream effectors of AKT most critically drive tumor progression versus metastasis in PI3K/AKT/mTOR-deregulated cancers?
Recent Trends
The field maintains 46,656 works with sustained interest in mTOR's metabolic roles, as reflected in the high citations of Saxton and Sabatini "mTOR Signaling in Growth, Metabolism, and Disease" (7123 citations) building on Laplante and Sabatini (2012) (8286 citations).
2017Emphasis persists on AKT regulation via rictor-mTOR per Sarbassov et al. , alongside PI3K pathway oncology from Vivanco and Sawyers (2002).
2005No recent preprints or news coverage available signals steady incorporation into broader cancer signaling research.
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