Acquired tumor cell resistance to sunitinib by increased invasion and epithelial-mesenchymal transition in LL/2 murine lung cancer

Abstract

Objective: This study aims to investigate biological behavior changes in a murine lung cancer cell characterized by acquired resistance to sunitinib, a potent inhibitor of multiple-targeted receptor tyrosine kinase.

Methods: A lung cancer cell line resistant to sunitinib (LL/2-R) was developed from its parental cell line (LL/2-P). Differences in biological characteristics and associated molecular profiles between these two cells were compared in vitro and in vivo.

Results: LL/2-R cells showed an approximately 5-fold higher IC₅₀ of sunitinib than LL/2-P cells and exhibited a reduced growth inhibition following sunitinib treatment compared with LL/2-P. In LL/2-R cells and tumors, increased migration, invasion and metastasis were observed, along with upregulation of MMP-2 and MMP-9. We also analyzed the molecular profiles involved in EMT, and found that E-cadherin was downregulated in LL/2-R tumors, and vimentin was upregulated in LL/2-R cells and tumors, along with β-catenin translocating to the nuclei in LL/2-R cells. Furthermore, transcriptional factors mediated EMT, snail and twist, and the secretion of TGFβ1 also increased in LL/2-R cells and tumors.

Conclusions: We established a sunitinib-resistant lung cancer cell line and confirmed its drug-resistance to sunitinib in vivo. Our results implied that increased invasion and EMT may associate with the acquisition of resistant phenotype to sunitinib in cancer cells.