Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies.
Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies.
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DOI：
10.1158/1078-0432.ccr-15-1762
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Herlyn M
中科院分区：
文献类型：
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作者：
Krepler C;Xiao M;Sproesser K;Brafford PA;Shannan B;Beqiri M;Liu Q;Xu W;Garman B;Nathanson KL;Xu X;Karakousis GC;Mills GB;Lu Y;Ahmed TA;Poulikakos PI;Caponigro G;Boehm M;Peters M;Schuchter LM;Weeraratna AT;Herlyn M
基于基因组和蛋白质组数据，在患者来源的异种移植(PDX)模型中测试二线个性化药物组合疗法。我们从BRAF抑制剂进展性黑色素瘤患者中建立了12个PDX。扩增后，用靶向测序和反相蛋白质阵列(RPPA)分析PDX。通过多臂临床前试验设计，我们确定了有效的精准医学方法。我们发现了以前被描述为耐药性驱动因素的改变：3个PDX的NRAS突变，2个MAP2K1(MEK1)突变，4个BRAF扩增，7个PTEN异常。在蛋白质水平上，磷酸化MAPK的重新激活占主导地位，同时PI3K在一个亚群中平行激活。PAN-PI3K抑制剂BKM120与BRAF(Encorafenib)/MEK(Binimetinib)抑制剂或ERK抑制剂VX-11e联用的二线疗效在体内得到证实。在3个PDX模型中观察到MET的扩增，其频率高于预期，可能是一种新的耐药机制。重要的是，MET扩增本身并不能预测MET抑制剂卡马替尼的敏感性。相比之下，卡马替尼作为单一药物在对BRAF/MEK联合治疗和高pMET耐药的PDX中导致显著但短暂的肿瘤消退。卡马替尼/恩可拉非尼/比尼美替尼三联用药在所有动物中均导致肿瘤不完全和持续消退。基因组和蛋白质组数据整合确定了双核心通路抑制以及满足组合靶点。这些研究为生物标记物的开发提供了证据，以适当地选择患者的个性化治疗方法，避免治疗失败。
To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models. We established 12 PDX from BRAF inhibitor progressed melanoma patients. Following expansion, PDX were analyzed using targeted sequencing and reverse phase protein arrays (RPPA). By using multi-arm pre-clinical trial designs, we identified efficacious precision medicine approaches. We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDX, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho MAPK predominated, with parallel activation of PI3K in a subset. Second line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib) /MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo. Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted incomplete and sustained tumor regression in all animals. Genomic and proteomic data integration identifies dual core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select patients' personalized therapies and avoid treatment failures.