Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

Abstract

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

“…Currently, TKIs are the first-line targeted treatment for ccRCC 26 . The acquired resistance to TKIs in ccRCC has become the major obstacle for improving the survival of ccRCC patients 27 . Thus, we aimed to study the specific role of OTUD1 in regulating the sensitivity of renal cancer cells to TKIs.…”

Analysis and Prediction of the Survival Trends of Patients with Clear-Cell Renal Cell Carcinoma: A Model-Based Period Analysis, 2001-2015

“…However, despite the adoption of multiple treatment modes, no significant progress was made to improve the prognosis of patients with ccRCC during the 15-year study period, and drug intolerance and many side effects are still inevitable. 5 , 27 , 30 , 31 This highlights the urgency of continuing to develop new and more specific treatments to improve the prognosis of ccRCC.…”

Renal clear cancer cells regulate the differentiation of urine‐derived stem cells to carcinoma‐associated fibroblasts via RUNX3/TGF‐β1 signaling axis

“…Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of renal cancer due to limited clinically effective treatments and being highly unresponsive to chemotherapy or radiotherapy (Garje et al, 2018). Nevertheless, tremendous advancements in exploring diverse therapeutic options have resulted in targeted therapy, which has been demonstrated effective even against advanced ccRCC (Armesto et al, 2021; Meng et al, 2021; Wei et al, 2021). The targeted therapy mainly acts by inhibiting the tumor progression by selectively constraining the vascular endothelial growth factor receptor and platelet‐derived growth factor receptor (PDGFR) towards preventing tumor angiogenesis and subsequent tumor metastasis (Liu et al, 2022; Reustle et al, 2020; Wang et al, 2022).…”