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Target: PIK3CD


Research on the Target PIK3CD

1. Target Summary:

PIK3CD encodes the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), which is a critical component of the PI3K signaling pathway involved in various cellular processes such as growth, survival, and metabolism. Dysregulation of PIK3CD is associated with several diseases, including autoimmune disorders and various cancers, particularly hematological malignancies. Activating mutations in PIK3CD can lead to activated phosphoinositide 3-kinase delta syndrome (APDS), characterized by immune deficiency and dysregulation.

2. Mechanism:

PIK3CD is part of the class IA PI3K family, which is activated by receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). Upon activation, PIK3CD catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), a lipid second messenger that recruits and activates downstream signaling proteins, including AKT (protein kinase B) and mTOR (mechanistic target of rapamycin). This signaling cascade regulates various cellular functions, including cell growth, proliferation, survival, and metabolism (Dornan GL, Burke JE, 2018; Liu X, Li X, Huang W, 2025).
In the context of cancer, PIK3CD activation can lead to enhanced cell survival and proliferation, contributing to tumorigenesis. In immune cells, dysregulation of PIK3CD signaling can result in impaired immune responses and increased susceptibility to infections, as seen in APDS (Maccari ME, Wolkewitz M, Schwab C, 2023).

3. Approved Drugs:

Currently, the selective PI3Kδ inhibitor leniolisib has been approved for the treatment of APDS. It has shown efficacy in normalizing immune function and reducing lymphoproliferation in patients with PIK3CD mutations (Rao VK, Kulm E, Grossman J, 2024).

4. Hypotheses:

  1. Role in Cancer: PIK3CD mutations contribute to the pathogenesis of various cancers, particularly hematological malignancies, by promoting cell survival and proliferation through the AKT/mTOR signaling pathway.
  2. Autoimmunity: Dysregulated PIK3CD signaling is hypothesized to lead to immune dysregulation and increased susceptibility to infections in patients with APDS.
  3. Therapeutic Target: Inhibiting PIK3CD may provide therapeutic benefits in treating conditions associated with its dysregulation, including cancers and autoimmune diseases (Carter MJ, Cox KL, Blakemore SJ, 2017).

5. Validation:

The role of PIK3CD in disease has been validated through various studies demonstrating its involvement in immune dysregulation and cancer. For instance, activating mutations in PIK3CD have been identified in patients with APDS, leading to immune deficiency and increased infection rates (Maccari ME, Wolkewitz M, Schwab C, 2023). Additionally, clinical trials of leniolisib have shown improvements in immune function and quality of life in patients with APDS, supporting the therapeutic targeting of PIK3CD (Rao VK, Kulm E, Grossman J, 2024).

6. Clinical Trials:

Ongoing clinical trials are investigating the efficacy of PIK3CD inhibitors in various contexts, including:
  • Leniolisib: A phase 3 trial has demonstrated its effectiveness in treating APDS, with significant improvements in immune function and quality of life (Rao VK, Kulm E, Grossman J, 2024).
  • Idelalisib: Another PI3Kδ inhibitor that has shown promise in treating B-cell malignancies, although it is primarily focused on PIK3CD's role in hematological cancers (Carter MJ, Cox KL, Blakemore SJ, 2017).

7. Involved Pathways:

PIK3CD is primarily involved in the PI3K/AKT/mTOR signaling pathway, which regulates cell growth, survival, and metabolism. Dysregulation of this pathway is implicated in various cancers and autoimmune diseases (Dornan GL, Burke JE, 2018).

8. Associated Genes:

  • PIK3CA: Encodes the p110α subunit of PI3K, often mutated in various cancers.
  • PIK3R1: Encodes the regulatory subunit p85α, which interacts with PIK3CD and is involved in the regulation of PI3K activity (Maccari ME, Wolkewitz M, Schwab C, 2023).

9. Target Expression:

PIK3CD is predominantly expressed in immune cells, including lymphocytes, where it plays a crucial role in regulating immune responses. Its expression is often upregulated in various cancers, contributing to tumorigenesis and immune evasion (Carter MJ, Cox KL, Blakemore SJ, 2017).

10. Additional Context:

Research on PIK3CD is rapidly evolving, with ongoing studies exploring its role in various diseases and potential therapeutic strategies. The development of gene therapies targeting PIK3CD mutations is also being investigated as a promising approach to treat APDS (Liu X, Li X, Huang W, 2025).

11. References:

  • Dornan GL, Burke JE. (2018). Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases. Frontiers in Immunology. PMID: 29616047.
  • Liu X, Li X, Huang W. (2025). Elucidating the pharmacological foundations and mechanisms of the Sihai Shuyu formula in treating Graves' disease. Frontiers in Endocrinology. PMID: 39950029.
  • Maccari ME, Wolkewitz M, Schwab C. (2023). Long-term treatment with selective PI3Kdelta inhibitor leniolisib in adults with activated PI3Kdelta syndrome. Blood Advances. PMID: 38593221.
  • Rao VK, Kulm E, Grossman J. (2024). Interim analysis: Open-label extension study of leniolisib for patients with APDS. The Journal of Allergy and Clinical Immunology. PMID: 37390899.
  • Carter MJ, Cox KL, Blakemore SJ. (2017). PI3Kdelta inhibition elicits anti-leukemic effects through Bim-dependent apoptosis. Leukemia. PMID: 27843137.