BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.
BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.
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DOI：
10.1016/j.celrep.2016.05.064
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发表时间：
2016-06-28
期刊：
影响因子：
8.8
通讯作者：
Peeper DS
中科院分区：
文献类型：
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作者：
Kemper K;Krijgsman O;Kong X;Cornelissen-Steijger P;Shahrabi A;Weeber F;van der Velden DL;Bleijerveld OB;Kuilman T;Kluin RJC;Sun C;Voest EE;Ju YS;Schumacher TNM;Altelaar AFM;McDermott U;Adams DJ;Blank CU;Haanen JB;Peeper DS
黑色素瘤的治疗前景正在迅速改善。靶向抑制剂显示出有希望的结果，但耐药性往往限制了持久的临床反应。存在对允许机械耐药性研究和（组合）治疗优化的体内系统的需要。因此，我们在BRAF抑制剂治疗前和耐药发生后，建立了大量来源于BRAFV 600 E、NRASQ61或BRAFWT/NRASWT黑色素瘤转移瘤的患者来源异种移植物（PDX）。利用PDX作为无限来源的优势，我们筛选了肿瘤裂解物的耐药机制。我们在PDX和一个独立的患者队列中，在约10%的病例中鉴定出携带激酶结构域重复的BRAFV600E蛋白（BRAFV600E/DK）。虽然BRAFV600E/DK耗竭恢复了对BRAF抑制的敏感性，但泛RAF二聚化抑制剂有效地消除了BRAFV600E/DK表达细胞。这些结果说明了该PDX平台的实用性，并保证了BRAF二聚化抑制剂用于这组黑色素瘤患者的临床验证。患者来源的异种移植物（PDX）平台包括89个转移性黑素瘤肿瘤平台包括几个前维罗非尼和维罗非尼耐药的PDX BRAFV 600 E激酶结构域的复制被鉴定为耐药机制Pan-RAF二聚化抑制剂LY3009120消除了具有这种复制的黑素瘤细胞Kemper et al.已经建立了一个由89个转移性黑素瘤异种移植物组成的平台。利用这个集合作为资源，他们鉴定了一种含有重复激酶结构域的BRAFV600E蛋白。泛RAF二聚化抑制剂抑制表达该BRAF突变体的PDX的扩增。
The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAFV600E, NRASQ61, or BRAFWT/NRASWT melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAFV600E protein harboring a kinase domain duplication (BRAFV600E/DK) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAFV600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAFV600E/DK-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients. Patient-derived xenograft (PDX) platform comprises 89 metastatic melanoma tumors Platform includes several pre-vemurafenib and vemurafenib-resistant PDXs Duplication of the BRAFV600E kinase domain is identified as a resistance mechanism Pan-RAF dimerization inhibitor LY3009120 eliminates melanoma cells with this duplication Kemper et al. have built a platform composed of 89 metastatic melanoma xenografts. Using this collection as a resource, they identified a BRAFV600E protein harboring a duplicated kinase domain. A pan-RAF dimerization inhibitor suppresses expansion of PDXs expressing this BRAF mutant.