Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma.
Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma.
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mTOR 和 S6RP 的磷酸化可预测依维莫司对转移性肾细胞癌患者的疗效。
DOI：
10.1186/1471-2407-14-376
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发表时间：
2014-05-28
期刊：
影响因子：
3.8
通讯作者：
Guo J
中科院分区：
文献类型：
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作者：
Li S;Kong Y;Si L;Chi Z;Cui C;Sheng X;Guo J
肾细胞癌（renal cell cancer，RCC）的发病率在过去的十年中一直在增加，并且转移性RCC（metastatic RCC，mRCC）患者的5年生存率相当低。依维莫司（RAD 001），一种新的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，通常耐受性良好，并证明了抗VEGF难治性mRCC患者的临床获益。然而，选择可能受益于依维莫司的患者的因素在很大程度上仍然未知。在这里，我们的目的是探索可能受益于依维莫司治疗的mRCC患者的潜在分子指标。石蜡包埋的肿瘤组织标本来自18例接受依维莫司治疗前的mRCC患者，这些患者参加了在VEGF受体（VEGFR）-酪氨酸激酶抑制剂（TKI）难治性中国mRCC患者中进行的依维莫司1b期试验（clinicaltrials.gov，NCT 01152801）检测磷酸化AKT，mTOR，真核细胞起始因子4 E（eIF 4 E）结合蛋白-1（4 EBP 1）和40 S核糖体蛋白S6（S6 RP）。临床获益率（完全缓解[CR]、部分缓解[PR]加上疾病稳定[SD] ≥ 6个月）和无进展生存时间（PFS）与这些mTOR相关分子的表达水平相关。这18例患者中，PR 1例，SD 15例（其中SD ≥ 6个月9例），疾病进展（PD）2例。临床获益率（CBR）为55.6%（10/18），中位PFS时间为8.4个月。磷酸化mTOR阳性表达患者的CBR（71.4%vs0%，P = 0.023）和PFS时间（11.3vs3.7个月，P = 0.001）均优于阴性表达患者。磷酸化S6 RP表达阳性患者的中位PFS长于磷酸化S6 RP表达阴性患者（11.3 vs 3.7个月，P = 0.002）。然而，磷酸-4EBP 1和磷酸-AKT的表达水平与依维莫司治疗的CBR和PFS疗效无关。磷酸化mTOR、S6 RP和/或4 EBP 1的共表达可提高生物标志物对接受依维莫司治疗的患者的预测价值。磷酸化mTOR和磷酸化S6 RP的表达水平可能是依维莫司治疗mRCC患者疗效的潜在预测生物标志物。联合检测磷酸化mTOR、S6 RP和/或4 EBP 1可能是筛选对mTOR抑制剂敏感的mRCC患者的潜在策略。
The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment. Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules. In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of phosphorylated mTOR, S6RP and/or 4EBP1 may improve the predictive value of the biomarkers for patients treated with everolimus. The expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with mRCC. Combining examinations of phosphorylated mTOR, S6RP and/or 4EBP1 may be a potential strategy to select mRCC patients sensitive to mTOR inhibitor treatment.
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影响因子：
11.5
作者：
Kong, Yan;Si, Lu;Guo, Jun
通讯作者：
Guo, Jun
DOI：
10.1073/pnas.1005320107
发表时间：
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影响因子：
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