WCLC 2025 - Posters & ePosters-P2.02.16 Identification of Deruxtecan-Induced Methylome Signature in NSCLC Cell Lines

Pdf Summary

This study identifies a unique DNA methylation signature induced by deruxtecan, a topoisomerase I inhibitor payload used in antibody-drug conjugates (ADCs) for treating non-small cell lung cancer (NSCLC). Given the need for predictive biomarkers to tailor ADC therapies, the researchers treated ten NSCLC cell lines with deruxtecan, cisplatin, or control at IC50 concentrations. Using an improved cell-free DNA methylome sequencing assay (cf-MethylSeq) profiling 144,400 genomic regions, they performed statistical analyses to identify differentially methylated regions (DMRs) specific to deruxtecan treatment compared to cisplatin or control.<br /><br />They discovered 30 hypermethylated DMRs uniquely associated with deruxtecan-treated cells, mapping to promoter regions of 64 genes; among these, 25 encode well-characterized proteins (e.g., DPYD, GATA2, TFAP2A, IL11). This methylome signature does not appear in cisplatin-treated cells, indicating specificity to deruxtecan rather than general chemotherapy effect. The findings represent the first methylation-based biomarker signature linked to deruxtecan response in NSCLC cell lines.<br /><br />The authors propose future validation of this methylome signature in plasma cell-free DNA from patients treated with Datopotamab deruxtecan (a TROP2 ADC) in ongoing clinical trials (TROPION-Lung01, -Lung05, -Pantumor01). Correlating circulating tumor DNA methylation patterns with clinical outcomes could establish a pharmacodynamic biomarker for ADC response, enabling personalized treatment strategies. This may include ex vivo assays or theranostic approaches deploying low-dose deruxtecan ADCs to predict therapeutic efficacy.<br /><br />In summary, this work delineates a novel, deruxtecan-specific DNA methylation signature in NSCLC cell lines that holds promise as a predictive biomarker to optimize ADC treatment and improve patient selection in clinical settings.

Asset Subtitle

Arjan Gower

Meta Tag

Speaker Arjan Gower

Topic Tumor Biology – Preclinical Biology

Keywords

DNA methylation signature

deruxtecan

topoisomerase I inhibitor

antibody-drug conjugates

non-small cell lung cancer

differentially methylated regions

cf-MethylSeq

predictive biomarker

Datopotamab deruxtecan

pharmacodynamic biomarker