logo
    Docs
 

Target: TOP2A


Research on the Target TOP2A

1. Target Summary:

TOP2A (Topoisomerase II alpha) is an essential enzyme involved in DNA replication, transcription, and chromatin remodeling. It plays a critical role in managing DNA topology by introducing double-strand breaks, allowing for the unwinding and re-ligation of DNA strands. TOP2A is highly expressed in various malignancies, including breast cancer, lung adenocarcinoma, and hepatocellular carcinoma, and is associated with poor prognosis and treatment resistance. Its overexpression makes it a promising target for cancer therapy, particularly in combination with other agents.

2. Mechanism:

TOP2A functions by creating transient double-strand breaks in DNA, which are necessary for the relaxation of supercoiled DNA during replication and transcription. This process is crucial for maintaining genomic stability. The enzyme operates through a cycle of binding to DNA, cleaving it, passing another segment of DNA through the break, and then resealing the break.
In cancer, the activity of TOP2A can lead to chromosomal translocations and mutations, contributing to tumorigenesis. The enzyme is a target for several chemotherapeutic agents, such as anthracyclines (e.g., doxorubicin) and etoposide, which inhibit its function, leading to increased DNA damage and apoptosis in cancer cells.
Recent studies have also highlighted the role of TOP2A in regulating cellular processes such as proliferation and the epithelial-mesenchymal transition (EMT), particularly in hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) (Wu et al., 2023; Wang et al., 2023).

3. Approved Drugs:

  • Doxorubicin: An anthracycline antibiotic that intercalates into DNA and inhibits TOP2A, leading to DNA damage and apoptosis.
  • Etoposide: A podophyllotoxin derivative that inhibits TOP2A, causing DNA strand breaks and cell death.
  • Other TOP2A inhibitors: Various investigational drugs targeting TOP2A are in clinical trials, including combinations with novel agents to enhance therapeutic efficacy.

4. Hypotheses:

  1. TOP2A as a Biomarker: High expression levels of TOP2A correlate with poor prognosis in various cancers, suggesting it could serve as a biomarker for disease progression and treatment response (Zhou et al., 2025).
  2. Combination Therapy: Targeting TOP2A in combination with other therapies (e.g., EZH2 inhibitors) may enhance treatment efficacy and overcome resistance in aggressive cancers (Kirk et al., 2015).
  3. Role in Immunotherapy: TOP2A may influence the efficacy of immunotherapy by modulating immune checkpoint expression and tumor microenvironment interactions (Wu et al., 2023).

5. Validation:

The role of TOP2A in cancer has been validated through various studies demonstrating its association with poor prognosis and treatment resistance. For instance, overexpression of TOP2A has been linked to aggressive tumor behavior in breast cancer and HCC (Zhou et al., 2025; Wang et al., 2023). Additionally, clinical trials have shown that patients with high TOP2A expression may benefit from TOP2A-targeted therapies, reinforcing its potential as a therapeutic target (Chen et al., 2024).

6. Clinical Trials:

Several clinical trials are investigating the efficacy of TOP2A-targeted therapies:
  • FUTURE Trial (NCT03805399): This trial evaluates the efficacy of targeted therapies in refractory metastatic triple-negative breast cancer, with a focus on molecular subtyping and genomic biomarkers, including TOP2A (Jiang et al., 2021).
  • Ongoing trials are assessing the combination of TOP2A inhibitors with other agents in various cancer types, including ovarian cancer and lung cancer (Borella et al., 2024).

7. Involved Pathways:

TOP2A is involved in several key cellular pathways:
  • DNA Repair Pathways: TOP2A plays a crucial role in the repair of DNA double-strand breaks.
  • Cell Cycle Regulation: It is essential for proper chromosomal segregation during mitosis.
  • Epithelial-Mesenchymal Transition (EMT): TOP2A is implicated in the regulation of EMT, which is critical for cancer metastasis (Wu et al., 2023).

8. Associated Genes:

  • EZH2: An epigenetic modifier that regulates TOP2A expression and is involved in cancer progression (Wang et al., 2023).
  • miR-139-5p: A microRNA that targets TOP2A, influencing its expression and cellular senescence in HCC (Wang et al., 2023).

9. Target Expression:

TOP2A is overexpressed in various cancers, including breast cancer, lung adenocarcinoma, and hepatocellular carcinoma. Its expression levels are often correlated with tumor aggressiveness and poor clinical outcomes (Zhou et al., 2025; Borella et al., 2024).

10. Additional Context:

TOP2A's role in cancer biology extends beyond its enzymatic function; it is also involved in the regulation of gene expression and chromatin structure. Understanding the multifaceted roles of TOP2A in cancer can lead to the development of more effective therapeutic strategies and personalized medicine approaches.

11. References:

  • Borella, F., Fucina, S., & Seminara, Y. (2024). Targeting TOP2A in Ovarian Cancer: Biological and Clinical Implications. Current oncology (Toronto, Ont.).
  • Chen, Z., Vallega, K. A., & Wang, D. (2024). DNA topoisomerase II inhibition potentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small cell lung cancer models. The Journal of clinical investigation.
  • Jiang, Y. Z., Liu, Y., & Xiao, Y. (2021). Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial. Cell research.
  • Kirk, J. S., Schaarschuch, K., & Dalimov, Z. (2015). Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer. Oncotarget.
  • Uuskula-Reimand, L., & Wilson, M. D. (2022). Untangling the roles of TOP2A and TOP2B in transcription and cancer. Science advances.
  • Wang, K., Jiang, X., & Jiang, Y. (2023). EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A. Journal of experimental & clinical cancer research.
  • Zhou, T., Niu, Y., & Li, Y. (2025). Advances in research on malignant tumors and targeted agents for TOP2A (Review). Molecular medicine reports.