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

Yerim Park·Soyeon Kim·Tae Min Kim·Miso Kim·Jeonghwan Youk·Dong-Wan Kim·Bhumsuk Keam
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Abstract

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 IC50 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 to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

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Actionable genomic alterationsAntibody&#x2013;drug conjugateNon-small cell lung cancerSacituzumab govitecanTROP2Journal Article

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Yerim Park, Soyeon Kim, Tae Min Kim, Miso Kim, Jeonghwan Youk, Dong-Wan Kim, Bhumsuk Keam. 2026-07-29. In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.. https://doi.org/10.1016/j.tranon.2026.102958

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