Integrated Molecular Characterization of Patient-Derived Models Reveals Therapeutic Strategies for Treating CIC-DUX4 Sarcoma.
Integrated Molecular Characterization of Patient-Derived Models Reveals Therapeutic Strategies for Treating CIC-DUX4 Sarcoma.
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DOI：
10.1158/0008-5472.can-21-1222
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发表时间：
2022-02-15
期刊：
影响因子：
11.2
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中科院分区：
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这项研究确定了CIC-DUX 4肉瘤中改变的HMGA 2/IGF 2BP/IGF 2信号传导，并为trabectedin和AKT/mTOR双重抑制剂联合治疗以特异性对抗该疾病提供了原则证据。Capicua-双同源异型框4（CIC-DUX 4）重排肉瘤（CDS）是非常罕见的，高度侵袭性的原发性肉瘤，代表了一个主要的治疗挑战。患者根据尤文肉瘤协议进行治疗，但强烈需要CDS特异性治疗。在这项研究中，对患者样本进行RNA测序，以确定将CDS与尤文肉瘤和其他融合驱动的肉瘤区分开的选择性特征。该特征用于验证新生成的CDS实验模型-患者来源的异种移植物（PDX）和PDX来源的细胞系-的代表性，并识别特定的治疗漏洞。差异表达基因的注释分析和分子基因验证突出了HMGA 2/IGF 2BP/IGF 2/IGF 1 R/AKT/mTOR轴，其表征CDS并使肿瘤对曲贝替丁和PI 3 K/mTOR抑制剂的组合治疗特别敏感。Trabectedin抑制IGF 2BP/IGF 2/IGF 1 R活性，但需要双重抑制PI 3 K和mTOR通路才能完全抑制下游信号传导介质。使用CDS PDX衍生的细胞系在体外和体内获得了双重AKT/mTOR抑制剂NVP-BEZ 235（dactolisib）与曲贝替定的组合的原理验证功效，证明了对局部肿瘤生长和多器官转移的强烈抑制。总体而言，代表性实验模型（PDX和PDX衍生细胞系）的开发有助于确定CDS对AKT/mTOR抑制剂和trabectedin的独特敏感性，揭示了对抗这种致命癌症的基于机制的治疗策略。这项研究确定了CIC-DUX 4肉瘤中改变的HMGA 2/IGF 2BP/IGF 2信号传导，并为trabectedin和AKT/mTOR双重抑制剂联合治疗以特异性对抗该疾病提供了原则证据。
This study identifies altered HMGA2/IGF2BP/IGF2 signaling in CIC-DUX4 sarcomas and provides proof of principle for combination therapy with trabectedin and AKT/mTOR dual inhibitors to specifically combat the disease. Capicua-double homeobox 4 (CIC-DUX4)–rearranged sarcomas (CDS) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. Patients are treated according to Ewing sarcoma protocols, but CDS-specific therapies are strongly needed. In this study, RNA sequencing was performed on patient samples to identify a selective signature that differentiates CDS from Ewing sarcoma and other fusion-driven sarcomas. This signature was used to validate the representativeness of newly generated CDS experimental models—patient-derived xenografts (PDX) and PDX-derived cell lines—and to identify specific therapeutic vulnerabilities. Annotation analysis of differentially expressed genes and molecular gene validation highlighted an HMGA2/IGF2BP/IGF2/IGF1R/AKT/mTOR axis that characterizes CDS and renders the tumors particularly sensitive to combined treatments with trabectedin and PI3K/mTOR inhibitors. Trabectedin inhibited IGF2BP/IGF2/IGF1R activity, but dual inhibition of the PI3K and mTOR pathways was required to completely dampen downstream signaling mediators. Proof-of-principle efficacy for the combination of the dual AKT/mTOR inhibitor NVP-BEZ235 (dactolisib) with trabectedin was obtained in vitro and in vivo using CDS PDX-derived cell lines, demonstrating a strong inhibition of local tumor growth and multiorgan metastasis. Overall, the development of representative experimental models (PDXs and PDX-derived cell lines) has helped to identify the unique sensitivity of the CDS to AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer. This study identifies altered HMGA2/IGF2BP/IGF2 signaling in CIC-DUX4 sarcomas and provides proof of principle for combination therapy with trabectedin and AKT/mTOR dual inhibitors to specifically combat the disease.