Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors.
Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors.
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DOI：
10.3389/fonc.2021.766298
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发表时间：
2021
影响因子：
4.7
通讯作者：
Thompson PA
中科院分区：
文献类型：
--
作者：
Gerson-Gurwitz A;Young NP;Goel VK;Eam B;Stumpf CR;Chen J;Fish S;Barrera M;Sung E;Staunton J;Chiang GG;Webster KR;Thompson PA
癌蛋白的表达在mRNA翻译水平上受到控制，并受真核生物翻译起始因子4F（eIF 4F）复合物的调节。eIF 4A是eIF 4F的一个组分，催化mRNA的5 '-非翻译区（5'-UTR）中二级结构的解旋，以促进核糖体扫描和翻译起始。佐他替芬（eFT 226）是一种选择性eIF 4A抑制剂，可增加eIF 4A与特异性多嘌呤序列基序之间的亲和力，据报道可抑制淋巴瘤模型中驱动癌基因的翻译。在这里，我们报告了在HER 2和FGFR 1/2受体酪氨酸激酶（RTK）的5 '-UTR中Zotatifin结合基序的鉴定。人类癌症中HER 2或FGFR 1/2的失调会导致PI 3 K/AKT和RAS/ERK信号通路的激活，从而增强eIF 4A活性并促进肿瘤细胞生长和生存所需的选定癌基因的翻译。在由HER 2或FGFR 1/2改变驱动的实体瘤模型中，佐他替芬下调癌蛋白表达可诱导持续的途径依赖性抗肿瘤活性，从而有效抑制细胞增殖、诱导细胞凋亡和显著的体内肿瘤生长抑制或消退。RTK驱动的肿瘤模型对佐他替芬的敏感性与高基础水平的mTOR活性和升高的翻译能力相关，突出了RTK驱动的信号通路产生的独特电路。这种依赖性确定了旨在垂直抑制PI 3 K/AKT/eIF 4F通路的合理组合策略的潜力。佐他替芬与PI 3 K或AKT抑制剂的组合通过阻断RTK驱动的耐药机制在RTK驱动的癌症模型中是有益的，证明了这些组合策略的临床潜力。
Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5’-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.