Abstract
BackgroundRenal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood.MethodsRCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients’ overall survival.ResultsWe demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinib-resistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models.ConclusionThis work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.
Highlights
Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment
Phenotypic variation between sunitinib-sensitive and resistant metastatic RCC of clear-cell histological sub-type (mccRCC) samples In order to investigate the mechanisms of sunitinib resistance, our laboratory has developed a sunitinibconditioned cell-line (Caki-1 Caki-1 sunitinib drug-conditioned (DC)) by conditioning the parental mccRCC cells, (Caki-1WT) [26]
There was a significant decrease in Caki-1 DC cell viability (~ 45%) in this sequential treatment compared to sunitinib monotherapy (~ 80%) (Fig. 5e, p < 0.001). These results suggest that downregulation of ATP-binding cassette sub-family B member 1 (ABCB-1) in mammalian target of rapamycin (mTOR)/Y-box binding protein 1 (YB-1) dependent pathway reverts sunitinib-resistance in mccRCC cells [34]
Summary
Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Resistance to tyrosine kinase inhibitors (TKIs) is a concerning phenomenon for renal cell carcinoma (RCC) patients. RCC is a highly vascular tumor and sunitinib is the most commonly used anti-angiogenic targeted agent that acts by inhibiting receptor tyrosine kinases in endothelial cells. Current treatment decision for mRCC is purely based on the clinical features: low risk patients are usually treated with anti-angiogenic tyrosine kinase inhibitors (TKIs) and intermediate/severe risk patients with immunotherapy [7, 8]. Initial responders to therapy will eventually develop resistance to TKIs within 10–14 months [3, 9]. Designing treatment strategies to overcome TKI resistance is challenging due to the lack of mechanistic insights and the availability of targeted therapies
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