FAK-Src复合物在促结缔组织增生小圆细胞瘤、尤文氏肉瘤和横纹肌肉瘤中的靶向作用

Q2 Medicine

Sarcoma Pub Date : 2022-05-11 DOI:10.1155/2022/3089424

A. V. van Erp, M. H. Hillebrandt-Roeffen, Niek van Bree, Tim A. Plüm, U. Flucke, I. Desar, E. Fleuren, W. V. D. van der Graaf, Y. Versleijen-Jonkers

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引用次数: 1

摘要

Desmoplastic小圆细胞瘤（DSRCTs）、尤因肉瘤（ES）、肺泡和胚胎性横纹肌肉瘤（ARMS和ERMS）是恶性肉瘤，通常发生在年轻时，在转移环境中预后较差。新的治疗方案是必要的。Src家族激酶抑制剂达沙替尼单剂治疗已在一项2期研究中对包括ES和RMS在内的晚期肉瘤患者进行了研究，但在这些亚型中作为单剂治疗失败。由于先前的研究表明RMS和ES组织和细胞系中的FAK和Src活性较高，并且达沙替尼治疗可上调活化的FAK，我们假设FAK-Src联合治疗可能是这些肿瘤类型的一种有趣的治疗选择。我们通过处理（p）FAK和（p）Src在DSRCT（n = 13），ES（n = 68），ARMS（n = 21）和ERMS（n = 39），并通过测定FAK抑制剂defactinib和多激酶（Abl/SFK）抑制剂达沙替尼在体外单独和联合治疗对每种亚型的细胞系的抗肿瘤作用。在DSRCT和ERMS模型中评估体内效应。在DSRCT（67%）、ES（6%）、ARMS（35%）和ERMS（19%）样本中观察到pFAK和pSrc同时表达（H-core>50）。Defactinib治疗降低了pFAK的表达，降低了所有亚型的细胞活力。达沙替尼治疗降低了每个亚型中pSrc的表达和细胞活力。联合治疗导致每个细胞系中pFAK和pSrc的完全减少，并在DSRCT、ERMS和ARMS中显示出增强的细胞活力降低、药物协同作用、DNA损伤诱导，以及更高的凋亡诱导趋势，但在ES细胞中没有。不幸的是，这些有希望的体外结果并没有转化为有希望的体内结果，因为我们没有观察到对体内肿瘤体积的显著影响，而且与达沙替尼单剂治疗相比，该组合也没有显示出优越的效果。

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Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and Rhabdomyosarcoma

Desmoplastic small round cell tumors (DSRCTs), Ewing sarcoma (ES), and alveolar and embryonal rhabdomyosarcoma (ARMS and ERMS) are malignant sarcomas typically occurring at young age, with a poor prognosis in the metastatic setting. New treatment options are necessary. Src family kinase inhibitor dasatinib single-agent treatment has been investigated in a phase 2 study in patients with advanced sarcomas including ES and RMS but failed as a single agent in these subtypes. Since previous studies demonstrated high FAK and Src activities in RMS and ES tissue and cell lines, and dasatinib treatment was shown to upregulate activated FAK, we hypothesized that FAK-Src combination treatment could potentially be an interesting treatment option for these tumor types. We examined the effects of targeting the FAK-Src complex by addressing (p)FAK and (p)Src expressions in tumor sections of DSRCT (n = 13), ES (n = 68), ARMS (n = 21), and ERMS (n = 39) and by determining the antitumor effects of single and combined treatment with FAK inhibitor defactinib and multikinase (Abl/SFK) inhibitor dasatinib in vitro on cell lines of each subtype. In vivo effects were assessed in DSRCT and ERMS models. Concurrent pFAK and pSrc expressions (H-score >50) were observed in DSRCT (67%), ES (6%), ARMS (35%), and ERMS (19%) samples. Defactinib treatment decreased pFAK expression and reduced cell viability in all subtypes. Dasatinib treatment decreased pSrc expression and cell viability in each subtype. Combination treatment led to a complete reduction in pFAK and pSrc in each cell line and showed enhanced cell viability reduction, drug synergy, DNA damage induction, and a trend toward higher apoptosis induction in DSRCT, ERMS, and ARMS but not in ES cells. These promising in vitro results unfortunately do not translate into promising in vivo results as we did not observe a significant effect on tumor volume in vivo, and the combination did not show superior effects compared to dasatinib single-agent treatment.

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来源期刊

Sarcoma Medicine-Radiology, Nuclear Medicine and Imaging

CiteScore

5.00

自引率

0.00%

发文量

审稿时长

14 weeks

期刊介绍： Sarcoma is dedicated to publishing papers covering all aspects of connective tissue oncology research. It brings together work from scientists and clinicians carrying out a broad range of research in this field, including the basic sciences, molecular biology and pathology and the clinical sciences of epidemiology, surgery, radiotherapy and chemotherapy. High-quality papers concerning the entire range of bone and soft tissue sarcomas in both adults and children, including Kaposi"s sarcoma, are published as well as preclinical and animal studies. This journal provides a central forum for the description of advances in diagnosis, assessment and treatment of this rarely seen, but often mismanaged, group of patients.