IKBKE regulates renal cell carcinoma progression and sunitinib resistance through the RRM2-AKT pathway.

Abstract

Tyrosine kinase inhibitors (TKIs), such as sunitinib, have emerged as promising agents in renal cell carcinoma (RCC) treatment, particularly in patients at advanced/metastatic clinical stages. However, acquired resistance to sunitinib is common following prolonged clinical treatment in RCC. Increasing evidence has demonstrated a strong correlation between inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) and cancer progression as well as drug resistance. Here, we found that IKBKE is upregulated in RCC tissues and sunitinib-resistant RCC cells. High IKBKE expression is positively correlated with advanced clinical staging and a poor prognosis in RCC. Silencing IKBKE downregulates ribonucleotide reductase M2 (RRM2) and induces cell cycle arrest at G2/M phase, suppressing RCC progression and enhancing sunitinib sensitivity to RCC cells. Mechanistically, IKBKE interacts with and phosphorylates RRM2 to activate the AKT signaling pathway to promotes RCC progression and sunitinib resistance. Notably, the IKBKE inhibitor CYT387 restores sunitinib sensitivity in RCC cells by downregulating RRM2 expression. Collectively, these results indicate that inhibition of IKBKE restrains RCC progression and enhances sunitinib sensitivity by downregulating RRM2 through the RRM2-AKT pathway, suggesting that IKBKE may be a potential therapeutic target for RCC.