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.

中文翻译：

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使用基于质谱（磷酸）蛋白质组学的晚期肾细胞癌患者的舒尼替尼治疗受益的候选生物标志物

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。