Phenotypic plasticity including drug efflux drives reversible irinotecan resistance in LIM1215 colorectal cancer cells

Date

2025-01-01

Author

Dilber, Tuğçe
Yalcin, Gizem Damla
Yılmaz, Kübra
Acar, Ahmet

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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Colorectal cancer (CRC) presents significant therapeutic challenges, particularly due to the development of resistance to standard chemotherapeutic agents such as irinotecan. In this study, we aimed to investigate the molecular and phenotypic mechanisms underlying irinotecan resistance in CRC using the LIM1215 cell line model. Transcriptomic analysis demonstrated that drug withdrawal induced major transcriptional reprogramming, characterized by downregulation of ABC transporters (ABCB1 and ABCG2), extracellular matrix-related genes, and markers of epithelial-to-mesenchymal transition (EMT), alongside reactivation of cell cycle pathways. Drug screening further indicated that resistant cells maintained under irinotecan pressure exhibited a multidrug-resistant phenotype, while withdrawn cells regained sensitivity, particularly to tyrosine kinase inhibitors. Supplementation with the efflux inhibitor Elacridar partially restored drug sensitivity in resistant cells, emphasizing the role of transporter-mediated efflux in maintaining resistance.

Subject Keywords

ABC transporters, colorectal cancer, irinotecan resistance, phenotypic plasticity

URI

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105020586102&origin=inward
https://hdl.handle.net/11511/116715

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Department of Biology, Article