ESTRO 2025 - Abstract Book

S3998

Radiobiology - Tumour radiobiology

ESTRO 2025

Purpose/Objective: Metabolic rewiring is one of the major hallmarks of cancer. 1 Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is known to be caused by genetic abnormalities, of which several have been linked to elevated serine/glycine metabolism, while nascent normal lung tissue hardly shows expression of serine/glycine pathway enzymes. 2,3 With increasing tumor grade, serine and glycine pathway enzymes are increasingly expressed in NSCLC and linked to poor prognosis. Approximately 37% of all lung cancers are metabolically rewired towards active serine and glycine production. Sertraline is a broadly used antidepressant, which we repurposed as anticancer drug acting as a dual specific serine hydroxymethyltransferase (SHMT) inhibitor. 4 SHMT is an enzyme controlling the bidirectional conversion of serine into glycine. Preclinically, in in vitro and in vivo lung cancer models, sertraline treatment lowered the intracellular and systemic glycine levels, which limits its integration into nucleotides and the antioxidant glutathione. 5 As such, we discovered that sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC. 5 Before proceeding to clinical trial, we evaluated whether sertraline affects common treatment regimen toxicity profiles in NSCLC. Material/Methods: Retrospective population-based study using data from the Belgian Cancer registry focused on stage IV NSCLC patients (incidence years 2016 – 2019) with respect to hospitalization-related (ICD-10-CM) grade 2-4 toxicities; anemia, neutropenia, thrombopenia, diarrhea and pneumonitis, irrespective of sertraline dosage. Patients with additional tumors or who underwent surgery were excluded. Sertraline usage was compared to other selective serotonin reuptake inhibitors (SSRI’s) and no SSRI treatment groups. Cox proportional hazards regression modeling defined hazard ratio’s related to main endpoint; toxicity of sertraline in combination with standard of care therapies relative to other SSRI or no SSRI usage. As secondary endpoint, we analyzed associations with three-year all-cause survival in NSCLC.