SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex.
SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex.
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DOI：
10.1158/0008-5472.can-15-0885
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发表时间：
2015-12-15
期刊：
影响因子：
11.2
通讯作者：
Ronai ZA
中科院分区：
文献类型：
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作者：
Feng Y;Pinkerton AB;Hulea L;Zhang T;Davies MA;Grotegut S;Cheli Y;Yin H;Lau E;Kim H;De SK;Barile E;Pellecchia M;Bosenberg M;Li JL;James B;Hassig CA;Brown KM;Topisirovic I;Ronai ZA
破坏真核生物翻译起始因子4F（eIF 4F）复合物提供了一种有吸引力的策略，可以增强现有癌症治疗的有效性，并克服对BRAF抑制剂（BRAFi）等药物的耐药性。在这里，我们鉴定并表征了小分子SBI-0640756（SBI-756），这是一种靶向eIF 4G 1并破坏eIF 4F复合物的一流抑制剂。SBI-756独立于mTOR损害eIF 4F复合物组装，并减弱BRAF抗性和BRAF非依赖性黑素瘤的生长。SBI-756还抑制AKT和NF-κB信号传导，但鉴定了小分子衍生物，其仅轻微影响这些途径，同时仍抑制eIF 4 F复合物形成和黑素瘤生长，说明SBI-756作为药物先导物的进一步结构和功能操纵的潜力。在SBI-756引起的基因表达特征模式中，DNA损伤和细胞周期调节因子是突出的，黑色素瘤细胞中的突变影响这些途径，从而产生耐药性。SBI-756在体外抑制NRAS、BRAF和NF 1突变型黑色素瘤的生长，在体内延迟Nras/Ink 4a黑色素瘤的发作并降低其发病率。此外，SBI-756和BRAFi的组合减弱了BRAFi抗性人类肿瘤的形成。总之，我们的研究结果显示了SBI-756如何消除BRAF非依赖性和BRAFi耐药黑色素瘤的生长，为评估其在其他癌症中的抗肿瘤作用提供了临床前依据。
Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage and cell cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF and NF1 mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Further, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers.