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- Title
Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation.
- Authors
Sakai, Iori; Miyake, Hideaki; Fujisawa, Masato
- Abstract
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 IC50 (concentration that reduces the effect by 50%) than that of ACHN/ P, was developed., Results ACHN/ R appeared to acquire significant cross resistance to sorafenib; however, there were no significant differences in sensitivities to the Mammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN/ P and ACHN/ R., After sunitinib treatment, the expression levels of phosphorylated Akt 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 Akt 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.
- Subjects
DRUG resistance in cancer cells; RENAL cell carcinoma; CELLULAR signal transduction; CELL proliferation; PROTEIN-tyrosine kinases
- Publication
BJU International, 2013, Vol 112, Issue 2, pE211
- ISSN
1464-4096
- Publication type
Article
- DOI
10.1111/j.1464-410X.2012.11655.x