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Target: POLE2


Research on the Target POLE2

1. Target Summary:

POLE2 (DNA polymerase epsilon 2, accessory subunit) is a critical component of the DNA polymerase epsilon complex, which plays a vital role in DNA replication and repair. It is implicated in various cancers, including colorectal, glioblastoma, esophageal squamous cell carcinoma, and oral squamous cell carcinoma. High expression levels of POLE2 are associated with poor prognosis and tumor progression, making it a potential therapeutic target.

2. Mechanism:

POLE2 functions as an accessory subunit of DNA polymerase epsilon, which is essential for DNA replication and repair. It enhances the enzyme's stability and activity, facilitating the synthesis of new DNA strands. In cancer cells, overexpression of POLE2 can lead to increased cell proliferation and survival by promoting DNA replication and repair mechanisms, thereby allowing cancer cells to thrive despite genomic instability.
Studies have shown that silencing POLE2 can inhibit cancer cell proliferation, migration, and invasion while promoting apoptosis. For instance, in oral squamous cell carcinoma (OSCC), POLE2 knockdown was found to inhibit the PI3K/AKT signaling pathway, leading to increased apoptosis and reduced tumor growth (Sun et al., 2023; Ge et al., 2023). Additionally, POLE2 has been linked to the stabilization of oncogenic proteins such as FOXM1, which further promotes malignant phenotypes in glioblastoma (Zhang et al., 2022).

3. Approved Drugs:

Currently, there are no specific drugs approved that directly target POLE2. However, some studies have explored the use of inhibitors that affect the broader DNA replication machinery, which may indirectly impact POLE2 activity. For example, the use of CHK1 inhibitors has shown potential in sensitizing cancer cells with low levels of B-family DNA polymerases, including POLE2 (Rogers et al., 2020).

4. Hypotheses:

  1. Oncogenic Role: POLE2 acts as an oncogene in various cancers, promoting tumor growth and survival through enhanced DNA replication and repair mechanisms.
  2. Therapeutic Target: Targeting POLE2 could provide a novel therapeutic strategy for cancers with high POLE2 expression, potentially improving treatment outcomes.
  3. Immune Response Modulation: POLE2 may influence immune cell infiltration and response in tumors, making it a candidate for combination therapies with immune checkpoint inhibitors (ICIs).

5. Validation:

The role of POLE2 as a therapeutic target has been validated through multiple studies demonstrating its overexpression in various cancers and its correlation with poor prognosis. For instance, high POLE2 expression has been linked to increased tumor progression and reduced survival rates in colorectal cancer and glioblastoma (Zhang et al., 2021; Sun et al., 2023). Additionally, the knockdown of POLE2 has consistently shown to inhibit cancer cell proliferation and promote apoptosis across different cancer types (Zhu et al., 2020; Jian & Zhang, 2024).

6. Clinical Trials:

POLE2 is involved in several clinical trials, particularly those focusing on cancers with POLE mutations. For example, a phase II clinical trial is investigating the efficacy of toripalimab, an anti-PD-1 antibody, in patients with advanced solid tumors harboring POLE mutations (ClinicalTrials.gov). Additionally, POLE status is included as an eligibility criterion in multiple ongoing trials, indicating its relevance in cancer treatment (My Cancer Genome).

7. Involved Pathways:

POLE2 is associated with several critical signaling pathways, including:
  • PI3K/AKT Pathway: Inhibition of this pathway upon POLE2 knockdown leads to increased apoptosis in cancer cells (Sun et al., 2023).
  • Wnt/beta-catenin Pathway: POLE2 silencing has been shown to affect this pathway, which is crucial for cell proliferation and differentiation (Jian & Zhang, 2024).
  • DNA Damage Response Pathways: POLE2 plays a role in maintaining genomic stability, and its dysregulation can lead to increased DNA damage and tumorigenesis.

8. Associated Genes:

POLE2 interacts with several other genes and proteins involved in DNA replication and repair, including:
  • FOXM1: An oncogenic transcription factor whose stability is influenced by POLE2 (Zhang et al., 2022).
  • STC1: A downstream target of POLE2 in renal cell carcinoma, promoting tumor growth (Zhang et al., 2021).
  • CDC6: Associated with immune infiltration in squamous cell lung cancer (PMC7191965).

9. Target Expression:

POLE2 is overexpressed in various cancers, including colorectal cancer, glioblastoma, and oral squamous cell carcinoma. Its expression levels correlate with tumor grade and patient prognosis, making it a potential biomarker for cancer progression (Zhang et al., 2021; Sun et al., 2023).

10. Additional Context:

The role of POLE2 in cancer biology highlights its potential as a therapeutic target. Its involvement in critical pathways and its association with poor prognosis underscore the need for further research into targeted therapies that can inhibit its function. Additionally, understanding its role in immune response may open avenues for combination therapies with immunotherapies.

11. References:

  • Sun, M. Y., Wang, L., & Shen, Z. Y. (2023). POLE2 Regulates Apoptosis of Oral Squamous Cell Carcinoma Cells through the PI3K/AKT Signaling Pathway. Current Medical Science.
  • Zhang, P., Chen, X., & Zhang, L. (2022). POLE2 facilitates the malignant phenotypes of glioblastoma through promoting AURKA-mediated stabilization of FOXM1. Cell Death & Disease.
  • Zhu, Y., Chen, G., & Song, Y. (2020). POLE2 knockdown reduces tumorigenesis in esophageal squamous cells. Cancer Cell International.
  • Jian, W., & Zhang, L. (2024). POLE2 silencing inhibits the progression of colorectal carcinoma cells via Wnt signaling axis. Cancer Biology & Therapy.
  • Rogers, R. F., Walton, M. I., & Cherry, D. L. (2020). CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells. Cancer Research.
  • ClinicalTrials.gov. (n.d.). Retrieved from ClinicalTrials.gov.
  • My Cancer Genome. (n.d.). Retrieved from My Cancer Genome.