Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma.
Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma.
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DOI：
10.1038/sj.bjc.6602646
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发表时间：
2005-06-20
影响因子：
8.8
通讯作者：
Drabkin HA
中科院分区：
文献类型：
--
作者：
Gemmill RM;Zhou M;Costa L;Korch C;Bukowski RM;Drabkin HA
表皮生长因子受体(EGFR)和肿瘤生长因子α(α)在肾癌中经常过度表达，但对单药EGFR抑制剂的反应并不常见。虽然von Hippel-Lindau(VHL)突变占主导地位，但结节性硬化症(TSC)患者也会发生肾癌。结节性硬化症突变激活哺乳动物雷帕霉素靶标(MTOR)，在生物化学上类似于VHL的改变。我们发现，肾癌细胞系在几乎没有其他ErbB家族成员的情况下表达EGFR mRNA。EGFR和mTOR联合抑制以VHL依赖的方式协同损害生长。易瑞沙可特异性阻断wt-VHL细胞ERK1/2的磷酸化，而雷帕霉素则抑制磷酸化的RPS6和4E-BP1，而与VHL无关。相反，磷酸化AKT对这些药物具有抵抗力，除非AKT被抑制，否则MYC翻译起始(多聚体结合)同样不受影响。原代RCCS细胞株含有相似数量的磷酸化ERK1/2，更高水平的ErbB-3，更少的磷酸化AKT，以及没有证据表明磷酸化RPS6，这表明mTOR活性降低。在没有上游激活的情况下，部分肿瘤和细胞系表达升高的eIF4E。尽管EGFR mRNA的量相似，但细胞系(VS肿瘤)过度表达EGFR蛋白。在配对的细胞系PRC3和WT8中，VHL突变体的EGFR蛋白转录后上调，EGF刺激的磷酸化延长。我们认为联合使用EGFR和mTOR抑制剂可能对合并wt-VHL的肾癌有用。然而，原发肿瘤和细胞系之间的明显差异需要进一步研究。
Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFα) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel–Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
11.4
作者：
Drabkin, H;Parsy, C;Roche, J
通讯作者：
Roche, J
影响因子：
8
作者：
Castagnino, P;Lorenzi, MV;Bottaro, DP
通讯作者：
Bottaro, DP
DOI：
10.1016/j.ijrobp.2003.09.098
发表时间：
2004-03-01
影响因子：
7
作者：
Foon, KA;Yang, XD;Schwab, GM
通讯作者：
Schwab, GM
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK