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Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation
Author(s) -
Sakai Iori,
Miyake Hideaki,
Fujisawa Masato
Publication year - 2013
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2012.11655.x
Subject(s) - sunitinib , sorafenib , cancer research , tyrosine kinase inhibitor , signal transduction , downregulation and upregulation , renal cell carcinoma , receptor tyrosine kinase , tyrosine kinase , kinase , cell growth , pharmacology , biology , medicine , microbiology and biotechnology , cancer , biochemistry , hepatocellular carcinoma , gene
What's known on the subject? and What does the study add? Although there have been a few studies investigating the molecular mechanism mediating the acquisition of resistance to molecular‐targeted agents, including sunitinib, by renal cell carcinoma ( RCC ) cells, this mechanism remains largely unclear. The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of a phenotype resistant to sunitinib in RCC , and additional treatment with agents targeting activated protein kinases could be a promising approach for overcoming resistance to sunitinib in RCC .Objective To characterise the mechanism involved in the acquired resistance to sunitinib, a potential inhibitor of multiple receptor tyrosine kinases ( RTKs ), in renal cell carcinoma ( RCC ).Materials and Methods A parental human RCC cell line, ACHN ( ACHN / P ), was continuously exposed to increasing doses of sunitinib, and a cell line resistant to sunitinib ( ACHN / R ), showing an ≈5‐fold higher IC 50 (concentration that reduces the effect by 50%) than that of ACHN / P , was developed.ResultsACHN / R appeared to acquire significant cross resistance to sorafenib; however, there were no significant differences in sensitivities to the M ammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN / P and ACHN / R . After sunitinib treatment, the expression levels of phosphorylated A kt and p44/42 mitogen‐activated protein kinase in ACHN / P , but not those in ACHN / R , were significantly inhibited. RTK assay showed that treatment of ACHN / P with sunitinib resulted in the marked downregulation of several phosphorylated RTKs compared with that of ACHN / R . Additional treatment with a specific inhibitor of A kt significantly increased the sensitivity of ACHN / R to sunitinib, but not that of ACHN / P . There were no significant differences between in vivo growth patterns of ACHN / P and ACHN / R in mice before and after the administration of sunitinib; however, the proportion of cells positive for TUNEL (terminal deoxynucleotidyl transferase‐mediated d UTP nick‐end labelling) staining in ACHN / P tumour was significantly greater than that in ACHN / R tumour in mice treated with sunitinib.Conclusion The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of resistant phenotype to sunitinib in RCC cells.