An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
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DOI：
10.1158/1535-7163.mct-14-0334
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发表时间：
2015-07-01
影响因子：
5.7
通讯作者：
Ludwig, Joseph A.
中科院分区：
文献类型：
--
作者：
Lamhamedi-Cherradi, Salah-Eddine;Menegaz, Brian A.;Ludwig, Joseph A.
尤文肉瘤是一种转录因子介导的儿科骨肿瘤，由EWSR 1基因和ETS转录因子家族中的几个基因之一（通常为FLI 1或ERG）的染色体易位引起。所产生的致癌融合蛋白的完全活性仅在结合RNA解旋酶A（RHA）后发生，并且设计用于干扰该相互作用的新型生物靶向小分子已经在临床前环境中显示出早期前景。在此，我们证明了口服生物可利用制剂YK-4-279的显著临床前抗肿瘤活性，并鉴定了可用于诱导附带敏感性的获得性化疗耐药机制。每日肠内给予YK-4-279导致小鼠模型中尤文肉瘤肿瘤生长的显著延迟。在预期的早期人体临床试验之前，我们研究了尤文肉瘤细胞逃避YK-4-279介导的细胞死亡的从头和获得性机制。通过长期体外暴露于水平稳定增加的YK-4-279形成的耐药克隆过度表达c-Kit、细胞周期蛋白D1、pStat 3（Y 705）和PKC亚型。有趣的是，观察到对伊马替尼和恩扎鲁肽（分别为c-Kit和PKC-β的选择性抑制剂）的交叉耐药性，并且在体外使用YK-4-279与恩扎鲁肽导致显著的药物协同作用，表明未来联合治疗的潜在作用。通过推进YK-4-279的口服制剂并确定突出的耐药机制，这项临床前研究使我们更接近治愈患有尤文肉瘤的青少年和年轻人的共同目标。(C)2015年AACR。
Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-beta, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. (C) 2015 AACR.