117 (Phospho)proteomics biomarkers for sunitinib response in RCC a: phosphosites upregulated in primary resistant patients (continued) Phosphosite p-value FC Role of corresponding protein in RCC PRMT1_Y263 0.030 3.3 Expression may be characteristic for low grade and low stage ccRCC, whole homologous loss of PRMT1 may be significant for high grade and high stage ccRCC89. BTG1 may inhibit cell growth and promote apoptosis by interacting with PRMT1 in RCC90. NPHP3_Y467 0.031 10.5 No literature describing a role in RCC. ALOX5_Y95 0.033 5.3 Higher expression predicts reduced survival in ccRCC91. Upregulation of ALOX5 is an important step in RCC progression. VEGF expression was strongly inducible by ALOX5 metabolites in vitro92. ALOX5 inhibition causes marked reduction of RCC cells in vitro through apoptosis93. PKP2_Y10 0.034 11.0 PKP2 is a target gene and component of a protein network regulated by HIF2α and is associated with a poorer survival of patients with RCC94. S E R I NC 5 _ Y345 0.038 9.8 No literature describing a role in RCC. ACTN4_Y265 0.045 4.4 No literature describing a role in RCC. SAMHD1_Y315 0.047 3.9 No literature describing a role in RCC. b: phosphosites upregulated in sensitive patients Phosphosite p-value FC Role of corresponding protein in RCC Uniquely identified in sensitive tumors PEAK1_Y635 n/a n/a No literature describing a role in RCC. EPHA2_Y575 n/a n/a Expression of EphA2 is positively associated with tumor size and Fuhrman nuclear grade in ccRCC64 and high expression is associated with poor disease outcome95. Enhanced YB1/EphA2 axis signaling promotes acquired resistance to sunitinib in RCC65. NCK2_Y110 n/a n/a No literature describing a role in RCC. TLN1_Y26 n/a n/a No literature describing a role in RCC. EGFR_Y1138 n/a n/a The epidermal growth factor receptor (EGFR) is overexpressed in RCC and it plays a critical role in tumorigenesis and progression in RCC96-98. EGFR hyperactivity in RCC is mediated by the VHL/HIF-2α/SMYD3 signaling cascade99. CTNND1_Y174 n/a n/a No literature describing a role in RCC. 4
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