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Target: PIK3CA


Research on the Target PIK3CA

1. Target Summary:

PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha) is a gene that encodes the p110α subunit of the phosphoinositide 3-kinase (PI3K) enzyme. It plays a crucial role in cellular functions such as growth, proliferation, and survival. Mutations in PIK3CA are among the most common oncogenic alterations found in various cancers, particularly breast cancer, where they are associated with tumor progression and resistance to therapies.

2. Mechanism:

PIK3CA mutations lead to the activation of the PI3K/AKT/mTOR signaling pathway, which is pivotal in regulating cell growth and survival. The mutations typically occur in hotspot regions of the gene, such as exons 9 and 20, resulting in gain-of-function alterations that promote oncogenic signaling.
  • Activation of PI3K Pathway: Mutant p110α enhances the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), leading to the activation of AKT (protein kinase B). This activation promotes cell survival, growth, and proliferation while inhibiting apoptosis (Mosele et al., 2020; Fillbrunn et al., 2022).
  • Therapeutic Resistance: PIK3CA mutations contribute to resistance against various therapies, including endocrine therapies in hormone receptor-positive breast cancer. Tumors may develop resistant subclones that adapt to pharmacologic inhibition, complicating treatment strategies (Canaud et al., 2021; Biology Insights, 2023).

3. Approved Drugs:

  • Alpelisib (Piqray): An α-selective PI3K inhibitor approved for use in combination with endocrine therapy for patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative breast cancer (FDA approval in 2019).
  • Capivasertib: An AKT inhibitor that has shown promise in combination with endocrine therapy for PIK3CA-mutant breast cancer (FDA approval pending).

4. Hypotheses:

  • Predictive Biomarker: PIK3CA mutations may serve as predictive biomarkers for treatment response in breast cancer, particularly in identifying patients who may benefit from PI3K inhibitors (Mosele et al., 2020).
  • Resistance Mechanism: The presence of PIK3CA mutations could indicate a higher likelihood of resistance to standard therapies, necessitating the use of targeted treatments (Fillbrunn et al., 2022).
  • Subtype-Specific Impact: The effect of PIK3CA mutations on prognosis and treatment response may vary depending on the breast cancer subtype, with distinct outcomes observed in hormone receptor-positive versus triple-negative breast cancers (Canaud et al., 2021).

5. Validation:

  • Clinical Studies: Numerous studies have validated the role of PIK3CA mutations as oncogenic drivers. For instance, a meta-analysis of 3,219 patients demonstrated that PIK3CA mutations are associated with poor prognosis in hormone receptor-positive breast cancer (Fillbrunn et al., 2022).
  • Functional Studies: Experimental models have shown that PIK3CA mutations lead to increased tumor growth and resistance to therapies, reinforcing their role as therapeutic targets (Mosele et al., 2020).

6. Clinical Trials:

  • SOLAR1 Trial: Evaluated the efficacy of alpelisib in combination with letrozole in patients with PIK3CA-mutated breast cancer, showing improved progression-free survival (PFS) compared to letrozole alone (NCT02437318).
  • NCI-MATCH Trial: Investigated the effectiveness of various targeted therapies, including PI3K inhibitors, in patients with PIK3CA mutations across multiple cancer types (NCT02465060).

7. Involved Pathways:

  • PI3K/AKT/mTOR Pathway: Central to the oncogenic effects of PIK3CA mutations, this pathway regulates cell growth, survival, and metabolism.
  • MAPK Pathway: PIK3CA mutations may also interact with the MAPK signaling pathway, contributing to tumor progression and resistance mechanisms (Canaud et al., 2021).

8. Associated Genes:

  • PTEN: A tumor suppressor gene that negatively regulates the PI3K pathway. Loss of PTEN function can exacerbate the effects of PIK3CA mutations, leading to increased tumorigenesis (Mosele et al., 2020).
  • AKT: The downstream effector of the PI3K pathway, which mediates many of the pro-survival signals activated by PIK3CA mutations.

9. Target Expression:

PIK3CA is expressed in various tissues, with higher expression levels observed in breast tissue. The frequency of mutations varies across different cancer types, with approximately 40% of hormone receptor-positive breast cancers harboring PIK3CA mutations (Fillbrunn et al., 2022).

10. Additional Context:

PIK3CA mutations are not only prevalent in breast cancer but also found in other malignancies, including colorectal, endometrial, and ovarian cancers. The understanding of PIK3CA's role in cancer biology continues to evolve, with ongoing research focused on developing more effective targeted therapies and understanding resistance mechanisms.

11. References:

  • Mosele, F., et al. (2020). "PIK3CA mutations in breast cancer: a review." Breast Cancer Research.
  • Fillbrunn, M., et al. (2022). "PIK3CA mutation status, progression and survival in advanced HR+/HER2- breast cancer: a meta-analysis." BMC Cancer.
  • Canaud, G., et al. (2021). "PIK3CA-related disorders: a review." Orphanet Journal of Rare Diseases.
  • Biology Insights. (2023). "PIK3CA Mutation in Breast Cancer: Vital Pathway Insights." Biology Insights.
  • NCI-MATCH Trial. (NCT02465060). "A Study of Targeted Therapy in Patients with Advanced Cancer." ClinicalTrials.gov.
  • SOLAR1 Trial. (NCT02437318). "Alpelisib in Combination with Letrozole in Patients with PIK3CA-Mutated Breast Cancer." ClinicalTrials.gov.