Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
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DOI：
10.1158/1078-0432.ccr-11-2683
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发表时间：
2012-05-01
影响因子：
11.5
通讯作者：
Bertotti, Andrea
中科院分区：
文献类型：
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作者：
Migliardi, Giorgia;Sassi, Francesco;Bertotti, Andrea
目的：沿Ras通路（KRAS， NRAS， BRAF, PIK3CA）的基因突变发生在大约50%的结直肠癌（CRC）中，并且与抗egf受体（EGFR）治疗的不良反应相关。我们评估了丝裂原活化蛋白(MAP)/细胞外信号调节激酶（ERK）激酶（MEK）和磷酸肌苷3激酶(PI3K)/mTOR抑制剂对Ras /RAF/ pik3ca突变转移性crc （mCRC）患者来源的异种移植物的影响，这些抑制剂可以中和主要的Ras效应物。实验设计：将40个携带KRAS、NRAS、BRAF和/或PIK3CA突变的mCRC样本植入非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠体内。每个异种移植物扩展到四个治疗组：安慰剂，MEK抑制剂AZD6244， PI3K/mTOR抑制剂，BEZ235或AZD6244 + BEZ235。最初用安慰剂治疗的病例会转移到AZD6244、BEZ235和抗egfr单克隆抗体西妥昔单抗。结果：在3周的评估时间点，AZD6244 + BEZ235联合治疗已建立的肿瘤在大多数病例（70%）中诱导疾病稳定，但未导致明显的肿瘤消退。单药治疗效果较差，BEZ235的活性高于AZD6244（疾病控制率，dcr: AZD6244, 27.5%; BEZ235, 42.5%）。西妥昔单抗三联治疗提供了进一步的优势（DCR, 88%）。在6周的评估时间点，疾病控制程度下降（dcr: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%）。交叉分析来自同一原始肿瘤的异种移植物小鼠并使用每种不同方式治疗显示亚组对AZD6244 (12.5%), BEZ235（35%）或AZD6244 + BEZ235（42.5%）具有优先敏感性；另一个亚组（10%）对任何治疗都表现出相同的反应。结论：MEK和PI3K/mTOR抑制所产生的普遍生长抑制作用表明，这种策略可能延缓患者的疾病进展。然而，数据提供了反对持久反应发生的警示性证据。临床癌症研究；18 (9);2515 - 25。(c) 2012年aacr。
Purpose: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti-EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC).Experimental Design: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab.Results: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment.Conclusions: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses. Clin Cancer Res; 18(9); 2515-25. (C) 2012 AACR.