Sunitinib Treatment Exacerbates intratumoral Heterogeneity in Metastatic Renal Cancer
Sunitinib Treatment Exacerbates intratumoral Heterogeneity in Metastatic Renal Cancer
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DOI：
10.1158/1078-0432.ccr-15-0207
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发表时间：
2015-09-15
影响因子：
11.5
通讯作者：
Powles, Thomas
中科院分区：
文献类型：
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作者：
Stewart, Grant D.;O'Mahony, Fiach C.;Powles, Thomas
目的：本研究的目的是探讨 VEGF 靶向治疗（舒尼替尼）对转移性透明细胞肾癌 (mccRCC) 肿瘤内分子异质性 (ITH) 的影响。实验设计：从接受舒尼替尼治疗（n = 23，SuMR 临床试验）或未治疗的 mccRCC 患者的原发性肾肿瘤中采集多个肿瘤样本（n = 187 个样本） （n = 23，SCORTRCC 研究）。使用无监督和监督分析（驱动突变、缺氧和基质相关基因）评估病理级 ITH、DNA (aCGH)、mRNA (Illumina Beadarray) 和候选蛋白（反相蛋白阵列）。使用肿瘤内蛋白质方差分布和个体患者 aCGH 分布以及基因表达聚类来分析 ITH。结果：与未治疗的肿瘤相比，治疗后的肿瘤等级异质性更大 (P = 0.002)。在无监督分析中，舒尼替尼治疗与 DNA 或 mRNA 中 ITH 的增加无关。然而，随着治疗的进行，驱动突变基因特征（DNA 和 mRNA）的 ITH 有所增加，并且蛋白质表达的变异性也有所增加（P < 0.05）。尽管存在这种变异性，治疗样本中仍发生了舒尼替尼关键靶标（例如 VHL、PBRM1 和 CAIX）的显着染色体和转录本变化。结论：这些研究结果表明，舒尼替尼治疗对 mccRCC 中关键肿瘤和治疗特异性基因/蛋白的表达和 ITH 具有显着影响。基于原发性肿瘤分析的结果并不支持耐药克隆在靶向治疗后被选择并占主导地位的假设。 (C) 2015 年 AACR。
Purpose: The aim of this study was to investigate the effect of VEGF-targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC).Experimental Design: Multiple tumor samples (n = 187 samples) were taken from the primary renal tumors of patients with mccRCC who were sunitinib treated (n = 23, SuMR clinical trial) or untreated (n = 23, SCOTRRCC study). ITH of pathologic grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia, and stromal-related genes). ITH was analyzed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene-expression clustering.Results: Tumor grade heterogeneity was greater in treated compared with untreated tumors (P = 0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (P < 0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1, and CAIX, occurred in the treated samples.Conclusions: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy. (C) 2015 AACR.