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TK216 靶向尤文肉瘤细胞中的微管。

TK216 targets microtubules in Ewing sarcoma cells.

机构信息

Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA; Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.

出版信息

Cell Chem Biol. 2022 Aug 18;29(8):1325-1332.e4. doi: 10.1016/j.chembiol.2022.06.002. Epub 2022 Jul 7.

DOI:10.1016/j.chembiol.2022.06.002
PMID:35803262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9394687/
Abstract

Ewing sarcoma (EWS) is a pediatric malignancy driven by the EWSR1-FLI1 fusion protein formed by the chromosomal translocation t(11; 22). The small molecule TK216 was developed as a first-in-class direct EWSR1-FLI1 inhibitor and is in phase II clinical trials in combination with vincristine for patients with EWS. However, TK216 exhibits anti-cancer activity against cancer cell lines and xenografts that do not express EWSR1-FLI1, and the mechanism underlying cytotoxicity remains unresolved. We apply a forward-genetics screening platform utilizing engineered hypermutation in EWS cell lines and identify recurrent mutations in TUBA1B, encoding ⍺-tubulin, that prove sufficient to drive resistance to TK216. Using reconstituted microtubule (MT) polymerization in vitro and cell-based chemical probe competition assays, we demonstrate that TK216 acts as an MT destabilizing agent. This work defines the mechanism of cytotoxicity of TK216, explains the synergy observed with vincristine, and calls for a reexamination of ongoing clinical trials with TK216.

摘要

尤因肉瘤（EWS）是一种儿科恶性肿瘤，由染色体易位 t(11;22)形成的 EWSR1-FLI1 融合蛋白驱动。小分子 TK216 被开发为一种首创的直接 EWSR1-FLI1 抑制剂，目前正在与长春新碱联合用于 EWS 患者的 II 期临床试验中。然而，TK216 对不表达 EWSR1-FLI1 的癌细胞系和异种移植物表现出抗癌活性，其细胞毒性的机制仍未解决。我们应用了一种利用 EWS 细胞系中工程化超突变的正向遗传学筛选平台，鉴定出编码 ⍺-微管蛋白的 TUBA1B 中反复出现的突变，这些突变足以驱动对 TK216 的耐药性。通过体外重建微管（MT）聚合和基于细胞的化学探针竞争测定，我们证明 TK216 是一种 MT 解聚剂。这项工作定义了 TK216 的细胞毒性机制，解释了与长春新碱观察到的协同作用，并呼吁重新审查正在进行的 TK216 临床试验。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/8c1223373784/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/1752e2b9f7ff/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/87f66b8eee80/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/5c44d39895df/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/84f4722d2dd7/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/8c1223373784/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/1752e2b9f7ff/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/87f66b8eee80/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/5c44d39895df/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/84f4722d2dd7/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbff/9394687/8c1223373784/gr4.jpg

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本文引用的文献

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