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Identification of thymidylate synthase as a potential therapeutic target for lung cancer
K Takezawa1, I Okamoto, S Tsukioka
1Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Background:
Thymidylate synthase (TS), a key enzyme in the de novo synthesis of thymidine, is an important chemotherapeutic target for malignant tumours including lung cancer. Although inhibition of TS has an antiproliferative effect in cancer cells, the precise mechanism of this effect has remained unclear.
Methods:
We examined the effects of TS inhibition with an RNA interference-based approach. The effect of TS depletion on the growth of lung cancer cells was examined using colorimetric assay and flow cytometry.
Results:
Measurement of the enzymatic activity of TS in 30 human lung cancer cell lines revealed that such activity differs among tumour histotypes. Almost complete elimination of TS activity by RNA interference resulted in inhibition of cell proliferation in all tested cell lines, suggestive of a pivotal role for TS in cell proliferation independent of the original level of enzyme activity. The antiproliferative effect of TS depletion was accompanied by arrest of cells in S phase of the cell cycle and the induction of caspase-dependent apoptosis as well as by changes in the expression levels of cyclin E and c-Myc. Moreover, TS depletion induced downregulation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP), and it seemed to activate the mitochondrial pathway of apoptosis.
Conclusion:
Our data provide insight into the biological relevance of TS as well as a basis for clinical development of TS-targeted therapy for lung cancer.
Insights
Inhibiting thymidylate synthase (TS) stops lung cancer cell growth by triggering apoptosis and cell cycle arrest, regardless of initial enzyme levels. This research supports TS-targeted lung cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Thymidylate synthase (TS) is crucial for DNA synthesis and a target in lung cancer therapy.
- The exact mechanism by which TS inhibition affects cancer cell proliferation is not fully understood.
Purpose of the Study:
- To investigate the effects of thymidylate synthase (TS) inhibition on lung cancer cell proliferation.
- To elucidate the molecular mechanisms underlying TS depletion-induced antiproliferative effects.
Main Methods:
- Utilized RNA interference to deplete thymidylate synthase (TS) in human lung cancer cell lines.
- Assessed cell proliferation using colorimetric assays and flow cytometry.
- Analyzed cell cycle progression, apoptosis, and protein expression changes.
Main Results:
- TS activity varied across different lung cancer histotypes.
- Complete TS depletion inhibited proliferation in all tested cell lines, irrespective of initial TS levels.
- TS depletion induced S-phase arrest, caspase-dependent apoptosis, altered cyclin E and c-Myc expression, and activated the mitochondrial apoptosis pathway, including XIAP downregulation.
Conclusions:
- Thymidylate synthase (TS) plays a critical role in lung cancer cell proliferation.
- The findings provide a deeper understanding of TS's biological significance.
- This study offers a foundation for developing TS-targeted therapies for lung cancer.
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