Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma.
Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma.
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DOI：
10.1038/s41388-017-0122-y
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发表时间：
2018-05
期刊：
影响因子：
8
通讯作者：
Gladdy RA
中科院分区：
文献类型：
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作者：
McKinnon T;Venier R;Yohe M;Sindiri S;Gryder BE;Shern JF;Kabaroff L;Dickson B;Schleicher K;Chouinard-Pelletier G;Menezes S;Gupta A;Zhang X;Guha R;Ferrer M;Thomas CJ;Wei Y;Davani D;Guidos CJ;Khan J;Gladdy RA
横纹肌肉瘤(RMS)是最常见的儿科软组织肉瘤，预后停滞不前，需要新的治疗方法。RMS的基因组分析表明，受体酪氨酸激酶(RTK)/RAS/PI3K轴的改变是常见的，FGFR4经常突变或过度表达。尽管FGFR4是一种潜在的可药物受体酪氨酸激酶，但它在RMS中的功能尚不清楚。这项研究测试了FGFR4激活突变和过度表达对小鼠产生RMS的能力。小鼠肿瘤模型随后被用来发现潜在的治疗靶点，并在临床前环境中测试双重PI3K/mTOR抑制剂。具体地说，我们提供了第一个机制证据，表明最常见的人类RMS突变V550E或N535K与FGFR4wt过表达相比，具有不同的效力，因为表达FGFR4V550E的小鼠成肌细胞经历了更高的细胞转化率，植入小鼠体内，并迅速形成与人类RMS高度相似的肉瘤。高表达FGFR4V550E的小鼠肿瘤细胞与人RMS细胞系一起在体外进行剂量-反应药物筛选。根据目标类别对化合物进行分组，并使用剂量-反应曲线下面积的平均百分比(AUC)来确定效力。RMS细胞对PI3K/mTOR抑制剂高度敏感，尤其是GSK2126458(Omipalisib)是一种有效的FGFR4V550E肿瘤细胞和人RMS细胞活性的抑制剂。FGFR4V550E高表达成肌细胞和肿瘤细胞具有低纳摩尔GSK2126458EC50值。用小鼠和人RMS细胞系进行的质量细胞术验证了GSK2126458在单细胞分辨率下的特异性，减少了磷酸化Akt的丰度，并减少了下游mTOR效应器4EBP1、eIF4E和S6的磷酸化。此外，抑制PI3K/mTOR也显著抑制了体内RMS肿瘤的生长。因此，通过开发一个用于测试新疗法的临床前平台，我们确定PI3K/mTOR抑制是一种有希望的治疗这种毁灭性的儿童癌症的新疗法。
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and outcomes have stagnated, highlighting a need for novel therapies. Genomic analysis of RMS has revealed that alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K axis are common and that FGFR4 is frequently mutated or overexpressed. Although FGFR4 is a potentially druggable receptor tyrosine kinase, its functions in RMS are undefined. This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice. Murine tumor models were subsequently used to discover potential therapeutic targets and to test a dual PI3K/mTOR inhibitor in a preclinical setting. Specifically, we provide the first mechanistic evidence of differential potency in the most common human RMS mutations, V550E or N535K, compared to FGFR4wt overexpression as murine myoblasts expressing FGFR4V550E undergo higher rates of cellular transformation, engraftment into mice, and rapidly form sarcomas that highly resemble human RMS. Murine tumor cells overexpressing FGFR4V550E were tested in an in vitro dose–response drug screen along with human RMS cell lines. Compounds were grouped by target class, and potency was determined using average percentage of area under the dose–response curve (AUC). RMS cells were highly sensitive to PI3K/mTOR inhibitors, in particular, GSK2126458 (omipalisib) was a potent inhibitor of FGFR4V550E tumor-derived cell and human RMS cell viability. FGFR4V550E-overexpressing myoblasts and tumor cells had low nanomolar GSK2126458 EC50 values. Mass cytometry using mouse and human RMS cell lines validated GSK2126458 specificity at single-cell resolution, decreasing the abundance of phosphorylated Akt as well as decreasing phosphorylation of the downstream mTOR effectors 4ebp1, Eif4e, and S6. Moreover, PI3K/mTOR inhibition also robustly decreased the growth of RMS tumors in vivo. Thus, by developing a preclinical platform for testing novel therapies, we identified PI3K/mTOR inhibition as a promising new therapy for this devastating pediatric cancer.
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影响因子：
--
作者：
McKinnon T;Venier R;Dickson BC;Kabaroff L;Alkema M;Chen L;Shern JF;Yohe ME;Khan J;Gladdy RA
通讯作者：
Gladdy RA
影响因子：
6.2
作者：
Ognjanovic, Simona;Linabery, Amy M.;Charbonneau, Bridget;Ross, Julie A.
通讯作者：
Ross, Julie A.
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
影响因子：
12.7
作者：
Poeschl, Julia;Stark, Sebastian;Schueller, Ulrich
通讯作者：
Schueller, Ulrich
影响因子：
11.2
作者：
Chmielecki J;Bailey M;He J;Elvin J;Vergilio JA;Ramkissoon S;Suh J;Frampton GM;Sun JX;Morley S;Spritz D;Ali S;Gay L;Erlich RL;Ross JS;Buxhaku J;Davies H;Faso V;Germain A;Glanville B;Miller VA;Stephens PJ;Janeway KA;Maris JM;Meshinchi S;Pugh TJ;Shern JF;Lipson D
通讯作者：
Lipson D