RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway,Advanced Science

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RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway
Advanced Science ( IF 14.3 ) Pub Date : 2021-07-28 , DOI: 10.1002/advs.202100881
Wei Xiong _{1,

2} , Bin Zhang ₃ , Haixin Yu ₃ , Liang Zhu _{1,

2} , Lu Yi _{1,

2} , Xin Jin _{1,

2}

Affiliation

Renal cell carcinoma (RCC) is a malignant tumor of the kidneys. Approximately 70% of RCC cases are clear cell renal cell carcinoma with von Hippel–Lindau (VHL) gene mutation and activation of the vascular endothelial growth factor (VEGF) pathway. Tyrosine kinase inhibitors (TKIs) targeting VEGF have emerged as promising agents for RCC treatment. Apart from primary resistance, acquired resistance to TKIs after initial tumor regression is common in RCC. Recently, immune checkpoint inhibition, including PD-1/PD-L1 blockade, alone or in combination with TKIs has improved the overall survival of patients with RCC. Ribonucleotide reductase subunit M2 (RRM2) has been reported in many types of cancer and has been implicated in tumor progression. However, the role of RRM2 in TKIs resistance in RCC remains unclear. In this study, the authors have demonstrated that RRM2 is upregulated in sunitinib-resistant RCC cells and patient tissues. They also find that RRM2 stabilizes ANXA1 and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in RCC. Moreover, RRM2 regulated antitumor immune responses, and knockdown of RRM2 enhance the anti-tumor efficiency of PD-1 blockade in renal cancer. Collectively, these results suggest that aberrantly expressed RRM2 may be a promising therapeutic target for RCC.

中文翻译：

RRM2 通过稳定 ANXA1 和激活 AKT 通路来调节肾癌对舒尼替尼和 PD-1 阻断的敏感性

肾细胞癌（RCC）是肾脏的恶性肿瘤。大约 70% 的 RCC 病例是透明细胞肾细胞癌，伴有 von Hippel-Lindau (VHL) 基因突变和血管内皮生长因子 (VEGF) 通路激活。靶向 VEGF 的酪氨酸激酶抑制剂 (TKI) 已成为治疗肾细胞癌 (RCC) 的有希望的药物。除了原发性耐药之外，初始肿瘤消退后对 TKI 的获得性耐药在 RCC 中也很常见。最近，免疫检查点抑制，包括 PD-1/PD-L1 阻断，单独或与 TKI 联合使用，改善了 RCC 患者的总体生存率。据报道，核糖核苷酸还原酶亚基 M2 (RRM2) 存在于多种类型的癌症中，并且与肿瘤进展有关。然而，RRM2 在 RCC 中 TKI 耐药中的作用仍不清楚。在这项研究中，作者证明 RRM2 在舒尼替尼耐药的 RCC 细胞和患者组织中表达上调。他们还发现，RRM2 可以稳定 ANXA1，并独立于其核糖核苷酸还原酶活性激活 AKT 通路，从而促进 RCC 中的舒尼替尼耐药。此外，RRM2 调节抗肿瘤免疫反应，敲低 RRM2 可以增强 PD-1 阻断剂在肾癌中的抗肿瘤效率。总的来说，这些结果表明异常表达的 RRM2 可能是 RCC 的一个有前途的治疗靶点。

更新日期：2021-09-22

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