酪氨酸激酶抑制剂舒尼替尼是晚期肾细胞癌（RCC）患者的有效一线治疗药物。假设基于质谱的（磷酸、p-）蛋白质组学的功能读数将识别舒尼替尼治疗结果的预测生物标志物，对 26 名 RCC 患者的肿瘤组织进行了分析。 8 名患者患有原发性耐药 (RES) 肾细胞癌，18 名患者患有敏感性 (SENS) 肾细胞癌。鉴定出 78 个磷酸位点特征（p<<0.05，倍数变化>>2）； RES 中 22 个 p 位点上调（RES 中独特：BCAR3、NOP58、EIF4A2、GDI1），SENS 中 56 个 p 位点上调（35 个独特）。 EIF4A1/EIF4A2 在 (p-) 蛋白质组的 RES 中以及在独立队列中的转录组水平上差异表达。通过 INKA 测定推断的 MAPK3 (p = 0.026) 和 EGFR (p = 0.045) 激酶活性在 SENS 中较高。翻译后修饰特征富集分析表明，不同的p位点中心特征得到富集（p< 0.05），其中RES中的FGF1和催乳素途径以及SENS中的钒酸盐和凝血酶治疗途径最为显着。总之，RCC（磷酸化）蛋白质组揭示了与舒尼替尼耐药性和敏感性相关的不同 p 位点和激酶活性。需要进行独立验证来开发一种检测方法，用于预先识别对舒尼替尼具有内在耐药性的患者。© 2023。作者。

The tyrosine kinase inhibitor sunitinib is an effective first-line treatment for patients with advanced renal cell carcinoma (RCC). Hypothesizing that a functional read-out by mass spectrometry-based (phospho, p-)proteomics will identify predictive biomarkers for treatment outcome of sunitinib, tumor tissues of 26 RCC patients were analyzed. Eight patients had primary resistant (RES) and 18 sensitive (SENS) RCC. A 78 phosphosite signature (p < 0.05, fold-change > 2) was identified; 22 p-sites were upregulated in RES (unique in RES: BCAR3, NOP58, EIF4A2, GDI1) and 56 in SENS (35 unique). EIF4A1/EIF4A2 were differentially expressed in RES at the (p-)proteome and, in an independent cohort, transcriptome level. Inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) as determined by INKA was higher in SENS. Posttranslational modifications signature enrichment analysis showed that different p-site-centric signatures were enriched (p < 0.05), of which FGF1 and prolactin pathways in RES and, in SENS, vanadate and thrombin treatment pathways, were most significant. In conclusion, the RCC (phospho)proteome revealed differential p-sites and kinase activities associated with sunitinib resistance and sensitivity. Independent validation is warranted to develop an assay for upfront identification of patients who are intrinsically resistant to sunitinib.© 2023. The Author(s).