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Target: TYMS


Research on the Target TYMS (Thymidylate Synthase)

1. Target Summary:

Thymidylate synthase (TYMS) is a critical enzyme involved in the de novo synthesis of deoxythymidine monophosphate (dTMP), a precursor necessary for DNA replication and repair. It catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) to dTMP, utilizing 5,10-methylene tetrahydrofolate as a cofactor. TYMS is a significant target in cancer therapy, particularly for chemotherapeutic agents like 5-fluorouracil (5-FU) and pemetrexed, which inhibit its activity to disrupt DNA synthesis in rapidly dividing cancer cells.

2. Mechanism:

TYMS plays a pivotal role in nucleotide metabolism, specifically in the synthesis of thymidine, which is essential for DNA replication. The enzyme catalyzes the conversion of dUMP to dTMP, a reaction that is the only de novo pathway for thymidine production in mammalian cells. Inhibition of TYMS leads to depletion of dTMP, resulting in reduced dTTP levels, which ultimately impairs DNA synthesis and repair mechanisms, triggering cell cycle arrest and apoptosis in cancer cells.
The action of 5-FU, a commonly used chemotherapeutic agent, involves its conversion to active metabolites that mimic the natural substrate of TYMS, thereby competitively inhibiting the enzyme. This inhibition leads to a decrease in dTMP and dTTP levels, causing disruption in DNA synthesis and promoting cytotoxic effects in cancer cells (Ciszewski et al., 2022; Varghese et al., 2019).

3. Approved Drugs:

  • 5-Fluorouracil (5-FU): A pyrimidine analog that inhibits TYMS, widely used in treating various cancers, including colorectal, breast, and gastric cancers.
  • Pemetrexed: An antifolate drug that targets multiple enzymes involved in folate metabolism, including TYMS, primarily used in non-small cell lung cancer and mesothelioma.

4. Hypotheses:

  1. Resistance Mechanism: Elevated expression of TYMS is hypothesized to contribute to resistance against 5-FU and other TYMS-targeted therapies. Increased TYMS levels may allow cancer cells to overcome the cytotoxic effects of these drugs (Geng et al., 2024).
  2. Biomarker Potential: Variants in the TYMS gene, such as the 28 bp tandem repeat polymorphism, are hypothesized to serve as biomarkers for predicting patient responses to fluoropyrimidine-based chemotherapy, with lower expression genotypes associated with better clinical outcomes (Jennings et al., 2012).
  3. Role in Tumor Microenvironment: TYMS is believed to influence the tumor microenvironment by modulating the epithelial-mesenchymal transition (EMT), which is critical for cancer metastasis (Ciszewski et al., 2022).

5. Validation:

Numerous studies have validated the role of TYMS in cancer biology:
  • Expression Studies: High levels of TYMS expression have been correlated with poor prognosis in various cancers, including colorectal and pancreatic cancers (Fu et al., 2019).
  • Genetic Polymorphisms: Research has shown that specific polymorphisms in the TYMS gene are associated with treatment outcomes and toxicity in patients receiving fluoropyrimidine-based therapies (Oosterom et al., 2018).
  • Functional Studies: In vitro experiments have demonstrated that silencing TYMS expression impairs cell proliferation and invasion in cancer cell lines, supporting its role as a therapeutic target (Geng et al., 2024).

6. Clinical Trials:

Ongoing clinical trials are investigating the efficacy of TYMS inhibitors and the impact of TYMS genetic variants on treatment outcomes. For example, trials are assessing the correlation between TYMS polymorphisms and patient responses to 5-FU and capecitabine in colorectal cancer (Castro-Rojas et al., 2017).

7. Involved Pathways:

TYMS is involved in several metabolic pathways, including:
  • Folate Metabolism: TYMS is a key enzyme in the folate pathway, which is crucial for nucleotide synthesis.
  • DNA Replication and Repair: By providing dTMP, TYMS is essential for maintaining DNA integrity during replication and repair processes.

8. Associated Genes:

  • DPYD: Dihydropyrimidine dehydrogenase, another enzyme involved in pyrimidine metabolism, which interacts with TYMS in the context of fluoropyrimidine metabolism.
  • MTHFR: Methylenetetrahydrofolate reductase, which is involved in folate metabolism and has been studied alongside TYMS for its role in chemotherapy response.

9. Target Expression:

TYMS is overexpressed in various cancers, including colorectal, breast, and pancreatic cancers. Its expression levels are often correlated with tumor aggressiveness and patient prognosis, making it a potential biomarker for cancer diagnosis and treatment stratification (Geng et al., 2024; Koumarianou et al., 2014).

10. Additional Context:

The role of TYMS in cancer extends beyond its enzymatic function; it is also implicated in the regulation of cell proliferation, apoptosis, and the tumor microenvironment. Understanding the multifaceted role of TYMS in cancer biology can lead to the development of novel therapeutic strategies and improve patient outcomes.

11. References:

  1. Ciszewski WM, Chmielewska-Kassassir M, Wozniak LA. Thymidylate Synthase Overexpression Drives the Invasive Phenotype in Colon Cancer Cells. Biomedicines. 2022.
  2. Varghese V, Magnani L, Harada-Shoji N. FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression. Scientific Reports. 2019.
  3. Jennings BA, Kwok CS, Willis G. Functional polymorphisms of folate metabolism and response to chemotherapy for colorectal cancer, a systematic review and meta-analysis. Pharmacogenetics and Genomics. 2012.
  4. Geng Y, Xie L, Wang Y. Unveiling the oncogenic significance of thymidylate synthase in human cancers. American Journal of Translational Research. 2024.
  5. Oosterom N, Berrevoets M, den Hoed MAH. The role of genetic polymorphisms in the thymidylate synthase (TYMS) gene in methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. Pharmacogenetics and Genomics. 2018.
  6. Fu Z, Jiao Y, Li Y. TYMS presents a novel biomarker for diagnosis and prognosis in patients with pancreatic cancer. Medicine. 2019.