ALK ALK FUSIONS

在急性大细胞淋巴瘤（ALCL）中NPM-ALK融合突变的最初发现和特征描述之后，发现EML4-ALK融合是肺腺癌亚群的驱动突变。alk融合将c-末端alk激酶域与融合伙伴的n-末端区域结合在一起，此后在一系列癌症中发现，包括炎性肌成纤维细胞瘤、肾细胞癌、弥漫性大B细胞淋巴瘤和结直肠癌。\ n \n在环唑替尼的一期试验中，在具有特定EML4-ALK变异体的患者亚群中，有92%的应答率，高于整个ALK重排人群中的57%，但亚群数不足以将变异体类型与患者应答相关联。\ n \由于野生型alk表达受限，以及alk敲除小鼠中出现的轻度表型，alk融合是理想的靶点。ALK抑制剂TAE684用于ALK融合癌驱动因子的初步表征，而对ALK和MET具有高度选择性的小分子ATP竞争对手RTK抑制剂Crizotinib已被批准为ALK重组NSCLC的一线治疗药物。\ n \n所有重新排列定义了一个NSCLC亚型，占NSCLC病例的3-5%，其特点是年轻患者比例更高，从不吸烟者。EML4-ALK变异体1是NSCLC中最常见的ALK融合，是首次在体外和小鼠模型中发现和证明癌症驱动因素的特性。与标准化疗相比，在alk重排的非小细胞肺癌中对环唑替尼的一期研究显示总生存率增加。这些和其他初步结果促使在NSCLC中加速批准环唑替尼。继续的临床研究表明，在多臂研究中，环唑替尼优于化疗，并作为一线疗法。克赖佐替尼也被发现对使用克赖佐替尼的非小细胞肺癌患者仍然有益。此外，环唑替尼还可以增加ALK重排的非小细胞肺癌脑转移的颅内疾病控制。
Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. \n\nIn a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. \n\nDue to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. \n\nALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC.