In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations

作者：Yerim Park, Soyeon Kim, Tae Min Kim, Miso Kim, Jeonghwan Youk, Dong‐Wan Kim, Bhumsuk Keam · 发表于：Translational Oncology · 年份：2026 · DOI：10.1016/j.tranon.2026.102958 · 研究领域：Lung Cancer Treatments and Mutations、HER2/EGFR in Cancer Research、Melanoma and MAPK Pathways

Purpose The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. Materials and methods We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. Results SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG ( P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC 50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6–48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. Conclusion Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity t...