ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties.
ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties.
复制标题
DOI：
10.1158/1541-7786.mcr-18-0171
复制
发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Lovly CM
中科院分区：
文献类型：
--
作者：
Childress MA;Himmelberg SM;Chen H;Deng W;Davies MA;Lovly CM
在多种肿瘤类型中均检测到涉及间变性淋巴瘤激酶 (ALK) 的致癌酪氨酸激酶融合体。尽管已报道了 30 多种不同的 5' 融合伴侣基因，但 ALK 重排癌症的治疗是在不考虑存在哪个 5' 伴侣基因的情况下决定的。关于 5' 伴侣如何影响融合生物学或对 ALK 酪氨酸激酶抑制剂 (TKI) 的反应性的数据很少。基于 5' 伴侣影响融合蛋白的内在特性、影响致癌潜力的细胞功能以及对 ALK TKI 敏感性的假设，生成了稳定表达七种不同 ALK 融合变体的克隆 3T3 细胞系。使用生化和细胞测定来评估各种 ALK TKI 在临床使用中的功效、转化表型和生化特性 每一次融合。所有七种 ALK 融合都诱导软琼脂中焦点形成和集落，尽管程度不同。计算了不同 ALK TKI（克唑替尼、ensartinib、alectinib、lorlatinib）的 IC50，并且在测试的 7 个 ALK 融合中注意到药物敏感性的一致差异（5-10 倍）。最后，生化分析揭示了激酶活性和蛋白质稳定性之间的负相关性。这些结果表明 5' 融合伴侣发挥重要的生物学作用，影响对 ALK TKI 的敏感性。本研究表明 5' ALK 融合伴侣影响 ALK TKI 药物敏感性。由于在许多癌症中发现了许多其他激酶融合，并且通常具有重叠的融合伙伴，因此这些研究对其他激酶驱动的恶性肿瘤产生了影响。
Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5’ fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 5’ partner is present. There is little data addressing how the 5’ partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKIs). Based on the hypothesis that the 5’ partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC50s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5–10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 5’ fusion partner plays an important biological role that affects sensitivity to ALK TKIs. This study shows that the 5’ ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies.