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Target: POLD1


Research on the Target POLD1

1. Target Summary:

POLD1 (DNA polymerase delta 1) is a crucial enzyme involved in DNA replication and repair. It encodes the catalytic subunit of DNA polymerase delta, which plays a vital role in maintaining genomic stability. Mutations in POLD1 are associated with various cancers, including colorectal, endometrial, and breast cancers, and are linked to a high mutational burden that may enhance responses to immunotherapy.

2. Mechanism:

POLD1 functions primarily as a DNA polymerase, facilitating the synthesis of DNA during replication. It possesses a proofreading exonuclease activity that corrects errors made during DNA synthesis, thus ensuring high fidelity in DNA replication.
  • Stabilization of Oncogenes: POLD1 has been shown to stabilize the MYC oncogene in bladder cancer, promoting tumor proliferation and metastasis. This stabilization occurs through a mechanism where POLD1 binds to the MYC homology box, preventing its degradation by the FBXW7 ubiquitin ligase (Wang et al., 2023, PMID: 37105989).
  • Role in DNA Repair: POLD1 is integral to the DNA damage repair (DDR) pathway. It interacts with various proteins involved in base excision repair and mismatch repair, contributing to the repair of DNA lesions and maintaining genomic integrity (Zhao et al., 2021, PMID: 34868924).
  • Tumor Microenvironment: Elevated POLD1 expression has been associated with an immunosuppressive tumor microenvironment, facilitating tumor progression and resistance to therapies (Zhao et al., 2021, PMID: 34868924).

3. Approved Drugs:

Currently, there are no specific drugs targeting POLD1 directly approved for clinical use. However, therapies that exploit the high mutational burden associated with POLD1 mutations, such as immune checkpoint inhibitors (e.g., pembrolizumab), are being explored in clinical settings for tumors with POLD1 alterations (Nebot-Bral et al., 2017, PMID: 28846956).

4. Hypotheses:

  • Tumorigenesis: POLD1 mutations may lead to increased genomic instability, contributing to tumorigenesis through the accumulation of mutations and altered gene expression profiles.
  • Immunotherapy Response: Tumors with POLD1 mutations may exhibit a higher response rate to immunotherapy due to the increased neoantigen load resulting from the high mutational burden (Magrin et al., 2021, PMID: 34363023).
  • Biomarker Potential: POLD1 expression levels could serve as a prognostic biomarker, with higher levels correlating with poor outcomes in certain cancers (Zhao et al., 2021, PMID: 34868924).

5. Validation:

POLD1 has been validated as a significant factor in cancer biology through multiple studies linking its mutations and expression levels to clinical outcomes. For instance, POLD1 mutations have been associated with favorable prognoses in colorectal and endometrial cancers, particularly in the context of immunotherapy (Magrin et al., 2021, PMID: 34363023). Additionally, studies have shown that POLD1 mutations correlate with increased tumor mutational burden and microsatellite instability, which are predictive of immunotherapy responses (Zhu et al., 2022, PMID: 35261896).

6. Clinical Trials:

Several clinical trials are investigating the role of POLD1 mutations in cancer treatment, particularly focusing on their potential as biomarkers for immunotherapy. Trials are assessing the efficacy of immune checkpoint inhibitors in patients with POLD1 mutations across various cancer types, including colorectal and endometrial cancers (Magrin et al., 2021, PMID: 34363023).

7. Involved Pathways:

POLD1 is involved in several key pathways:
  • DNA Replication Pathway: Essential for the synthesis of new DNA strands during cell division.
  • DNA Damage Repair Pathway: Participates in base excision repair and mismatch repair, crucial for correcting DNA errors.
  • Cell Cycle Regulation: Influences cell cycle progression through its role in DNA synthesis and repair.

8. Associated Genes:

POLD1 is often studied alongside other genes involved in DNA repair and replication, such as:
  • POLE: Encodes the catalytic subunit of DNA polymerase epsilon, which works in conjunction with POLD1.
  • NTHL1: Another gene associated with hereditary cancer syndromes, particularly in the context of DNA repair deficiencies.

9. Target Expression:

POLD1 expression is typically elevated in various cancers, including colorectal, endometrial, and hepatocellular carcinoma. High levels of POLD1 are often associated with poor prognosis and an immunosuppressive tumor microenvironment (Zhao et al., 2021, PMID: 34868924).

10. Additional Context:

POLD1 mutations are part of a broader category of hereditary cancer predisposition syndromes. Understanding the role of POLD1 in cancer can help refine genetic testing and surveillance strategies for at-risk individuals. The identification of POLD1 as a potential therapeutic target opens avenues for personalized medicine approaches in oncology.

11. References:

  • Wang Y, Ju L, Wang G. DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. Nature Communications. 2023 Apr 27. PMID: 37105989.
  • Zhao S, Wei C, Tang H. Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma. Frontiers in Oncology. 2021. PMID: 34868924.
  • Magrin L, Fanale D, Brando C. POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes. Oncogene. 2021 Oct. PMID: 34363023.
  • Nebot-Bral L, Brandao D, Verlingue L. Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine. European Journal of Cancer. 2017 Oct. PMID: 28846956.
  • Zhu M, Cui H, Zhang L. Assessment of POLE and POLD1 mutations as prognosis and immunotherapy biomarkers for stomach adenocarcinoma. Translational Cancer Research. 2022 Jan. PMID: 35261896.