Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Ullevål, Norway.
Oncotarget. 2022 Aug 4;13:970-981. doi: 10.18632/oncotarget.28257. eCollection 2022.
Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.
激酶活性在肾细胞癌（RCC）中经常发生改变，酪氨酸激酶抑制剂（TKI）是转移性疾病患者标准治疗策略的一部分。然而，仍然没有确定的生物标志物来预测特定 TKI 的临床获益。在这里，我们使用 PamChip 技术进行了蛋白酪氨酸激酶（PTK）谱分析。本研究的目的是鉴定来自同一患者的正常和恶性肾组织之间的 PTK 活性差异，并研究临床上常用的 TKI（舒尼替尼、帕唑帕尼、卡博替尼和替沃扎尼）的抑制作用。简而言之，我们的结果表明，36 种激酶底物在正常和癌症肾组织之间存在差异（FDR<0.05），其中 Src 家族激酶和磷酸肌醇 3-激酶（PI3K）途径的成员在肾癌中表现出高活性。此外，用 TKI 治疗透明细胞 RCC 表明，Rap1、Ras 和 PI3K 途径等途径被强烈抑制，而神经生长因子途径在添加 TKI 后活性增加。在我们的实验中，与舒尼替尼和帕唑帕尼相比，替沃扎尼和卡博替尼对 PTK 活性的抑制作用更强，这意味着它们可能更适合作为某些 RCC 患者的 TKI。
