RRM2 Regulates Sensitivity to Sunitinib and PD‐1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway

• Published in: Advanced science Vol. 8; no. 18; pp. e2100881 - n/a
• Main Authors: Xiong, Wei, Zhang, Bin, Yu, Haixin, Zhu, Liang, Yi, Lu, Jin, Xin
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-09-2021; John Wiley and Sons Inc; Wiley
• Subjects: Angiogenesis; Annexin A1 - genetics; Annexin A1 - metabolism; Antineoplastic Agents - pharmacology; ANXA1; Cell Line; Humans; Hypoxia; Immune Checkpoint Inhibitors - pharmacology; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kinases; Medical prognosis; Metastasis; PD‐1 blockade; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Regression analysis; renal cell carcinomas; Ribonucleoside Diphosphate Reductase - genetics; Ribonucleoside Diphosphate Reductase - pharmacology; Ribonucleotide reductase; RRM2; Signal Transduction; Statistical analysis; Sunitinib - pharmacology; tyrosine kinase inhibitors; Vascular endothelial growth factor; Turkey; tyrosine kinase inhibitors; PD-1 blockade; ANXA1; RRM2; renal cell carcinomas
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202100881

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.
RRM2 overexpression plays a key role in sunitinib resistance in patients with renal cell carcinoma and that RRM2 competes with UBE3A to prevent ANXA1 degradation. The up‐regulated ANXA1 activates AKT signaling pathway to regulate the sensitivity to sunitinib and PD‐1 blockade in renal cancer cells.