logo
    Docs
 

Target: AKT1


Research on the Target AKT1

1. Target Summary:

AKT1, also known as Protein Kinase B (PKB), is a serine/threonine kinase that plays a crucial role in various cellular processes, including metabolism, cell proliferation, survival, and angiogenesis. It is a key component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, which is frequently dysregulated in various cancers and other diseases.

2. Mechanism:

AKT1 is activated by phosphorylation at two key residues (Thr308 and Ser473) through upstream kinases, primarily PDK1 and mTORC2. Once activated, AKT1 translocates to the plasma membrane, where it interacts with various substrates to regulate multiple cellular functions.
  • Cell Survival and Proliferation: AKT1 promotes cell survival by inhibiting apoptotic pathways through the phosphorylation of pro-apoptotic factors such as BAD and caspase-9, and by activating anti-apoptotic proteins like Bcl-2 (Fresno Vara et al., 2004).
  • Metabolism: AKT1 enhances glucose uptake by promoting the translocation of glucose transporter 4 (GLUT4) to the cell membrane and stimulates glycolysis by phosphorylating key glycolytic enzymes (Chen et al., 2024).
  • Angiogenesis: AKT1 promotes angiogenesis by activating endothelial cells and inducing the expression of vascular endothelial growth factor (VEGF) (Iida et al., 2020).
  • Immune Response: AKT1 is involved in macrophage polarization, influencing the balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes (Vergadi et al., 2017).

3. Approved Drugs:

  • Capivasertib: An AKT inhibitor approved for use in combination with fulvestrant for hormone receptor-positive advanced breast cancer (Turner et al., 2023).
  • Other Investigational Inhibitors: Various other AKT inhibitors are in clinical trials, targeting different cancer types and conditions.

4. Hypotheses:

  • Cancer Progression: AKT1 mutations may serve as biomarkers for cancer progression and treatment response, particularly in breast cancer and other malignancies (Nunnery & Mayer, 2020).
  • Non-Cancerous Diseases: AKT1 may play a significant role in metabolic disorders and inflammatory diseases, suggesting that targeting AKT1 could provide therapeutic benefits beyond oncology (He et al., 2018).
  • Therapeutic Targeting: Inhibiting AKT1 could enhance the efficacy of existing therapies by overcoming resistance mechanisms in cancer treatment (Nitulescu et al., 2016).

5. Validation:

AKT1 has been validated as a therapeutic target through numerous studies demonstrating its role in cancer biology and resistance to therapies. For instance, the efficacy of capivasertib in clinical trials has shown significant improvements in progression-free survival in patients with AKT pathway alterations (Turner et al., 2023). Additionally, AKT1's involvement in various signaling pathways supports its validation as a critical target in both cancer and non-cancerous diseases.

6. Clinical Trials:

  • CAPItello-291 Trial: A phase 3 trial evaluating capivasertib in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer, showing improved progression-free survival in patients with AKT pathway alterations (Turner et al., 2023).
  • Ongoing Trials: Numerous clinical trials are investigating the efficacy of AKT inhibitors in various cancers, including triple-negative breast cancer and other solid tumors (Pascual & Turner, 2019).

7. Involved Pathways:

  • PI3K/AKT/mTOR Pathway: The primary pathway involving AKT1, crucial for cell growth, survival, and metabolism.
  • MAPK Pathway: Interactions with the MAPK pathway have been noted, particularly in cancer progression (He et al., 2024).
  • Inflammatory Pathways: AKT1 is involved in modulating inflammatory responses through macrophage polarization (Vergadi et al., 2017).

8. Associated Genes:

  • PIK3CA: Frequently mutated in cancers, leading to hyperactivation of the PI3K/AKT pathway.
  • PTEN: A tumor suppressor that negatively regulates the PI3K/AKT pathway; loss of PTEN function can lead to AKT1 activation.
  • mTOR: A downstream target of AKT1 that regulates cell growth and metabolism.

9. Target Expression:

AKT1 is widely expressed in various tissues, with particularly high levels in the brain, liver, and muscle. Its expression can be upregulated in response to growth factors and insulin, linking it to metabolic processes.

10. Additional Context:

AKT1's role extends beyond cancer; it is implicated in metabolic disorders, cardiovascular diseases, and neurodegenerative conditions. For example, AKT1 has been shown to participate in the regulation of oxidative stress in Parkinson's disease (Cheng et al., 2022).

11. References:

  • Fresno Vara, J. A., Casado, E., & de Castro, J. (2004). PI3K/Akt signalling pathway and cancer. Cancer Treatment Reviews, 30(3), 193-204. PMID: 15023437.
  • Nunnery, S. E., & Mayer, I. A. (2020). Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer. Drugs, 80(11), 1091-1105. PMID: 32894420.
  • Turner, N. C., Oliveira, M., & Howell, S. J. (2023). Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. The New England Journal of Medicine, 388(22), 2115-2127. PMID: 37256976.
  • Vergadi, E., Ieronymaki, E., & Lyroni, K. (2017). Akt Signaling Pathway in Macrophage Activation and M1/M2 Polarization. Journal of Immunology, 198(3), 123-130. PMID: 28115590.
  • He, R. Q., Wu, P. R., & Xiang, X. L. (2022). CircSV2b participates in oxidative stress regulation through miR-5107-5p-Foxk1-Akt1 axis in Parkinson's disease. Redox Biology, 52, 102305. PMID: 35973363.
  • Iida, M., Harari, P. M., & Wheeler, D. L. (2020). Targeting AKT/PKB to improve treatment outcomes for solid tumors. Mutation Research, 786, 108335. PMID: 32120136.
  • Nitulescu, G. M., Margina, D., & Juzenas, P. (2016). Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use. International Journal of Oncology, 48(3), 883-895. PMID: 26698230.
This comprehensive overview provides a detailed understanding of AKT1, its mechanisms, therapeutic implications, and ongoing research efforts.