Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer
Anaís Sánchez-Castillo1, Elien Heylen2, Judith Hounjet1
1Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
Background:
Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy.
Methods:
We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures.
Results:
Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels.
Conclusion:
Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.
Insights
Targeting serine/glycine metabolism with sertraline plus radiotherapy inhibits non-small cell lung cancer (NSCLC) growth. This combination therapy restricts cancer cell recovery and enhances anti-tumor immunity in NSCLC models.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer immunology
Background:
- Non-small cell lung cancer (NSCLC) is a lethal malignancy with treatment resistance.
- Metabolic rewiring is a key cancer hallmark, but serine/glycine pathway adaptations to radiotherapy are poorly understood.
Purpose of the Study:
- To investigate serine/glycine pathway metabolite consumption in response to radiotherapy in NSCLC.
- To evaluate the efficacy of combining sertraline, a serine/glycine conversion inhibitor, with radiotherapy in NSCLC models.
Main Methods:
- Mass-spectrometry-based metabolomics was used to analyze plasma and cell lines from NSCLC patients and models.
- In vitro assays (proliferation, clonogenic, spheroid) and in vivo studies in an NSCLC mouse model were performed.
Main Results:
- Radiotherapy significantly consumed serine/glycine pathway metabolites in NSCLC.
- Combination therapy with sertraline and radiotherapy impaired NSCLC proliferation, clonogenicity, and stem cell renewal.
- In vivo, combination therapy reduced tumor growth, modulated systemic metabolites, and reshaped the tumor microenvironment towards natural killer cell-mediated immunity.
Conclusions:
- Targeting serine/glycine metabolism with sertraline restricts cancer cell recovery post-radiotherapy.
- Combination therapy provides tumor control in NSCLC through metabolic targeting and immunomodulation.
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