Liu Shiwei, Li Junhong, Zhang Junyu, Wan Fangning, Hong Zongyuan, Hong Zhe, Dai Bo
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Int J Biol Sci. 2024 Nov 11;20(15):6146-6161. doi: 10.7150/ijbs.102666. eCollection 2024.
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.
酪氨酸激酶抑制剂（TKIs），如舒尼替尼，已成为肾细胞癌（RCC）治疗中有前景的药物，特别是对于处于晚期/转移性临床阶段的患者。然而，在RCC患者长期临床治疗后，对舒尼替尼获得性耐药很常见。越来越多的证据表明，核因子κB激酶亚基ε（IKBKE）抑制剂与癌症进展以及耐药性之间存在密切关联。在此，我们发现IKBKE在RCC组织和对舒尼替尼耐药的RCC细胞中上调。IKBKE高表达与RCC的晚期临床分期和不良预后呈正相关。沉默IKBKE可下调核糖核苷酸还原酶M2（RRM2）并诱导细胞周期停滞在G2/M期，抑制RCC进展并增强RCC细胞对舒尼替尼的敏感性。机制上，IKBKE与RRM2相互作用并使其磷酸化，以激活AKT信号通路，促进RCC进展和舒尼替尼耐药。值得注意的是，IKBKE抑制剂CYT387通过下调RRM2表达恢复RCC细胞对舒尼替尼的敏感性。总体而言，这些结果表明，抑制IKBKE通过RRM2-AKT途径下调RRM2来抑制RCC进展并增强舒尼替尼敏感性，提示IKBKE可能是RCC的一个潜在治疗靶点。
