ALK EML4-ALK E6;A20

EML4-ALK变异体3a由融合到EML4外显子1-6的alk激酶域组成，而3b变异体在EML4和ALK区域之间有一个额外的33bp的内含子EML4序列。发现这两个变异源于一个单一的基因组重排，并且在大约30%的EML4-ALK阳性NSCLC中发现3a/3b。变体3a具有细胞质和核分布。在体外，这些变异体对ALK抑制剂TAE684和环唑替尼具有敏感性，但其敏感性低于其他EML4-ALK变异体。H2228细胞系包含3a和3b变异体，被描述为对alk抑制具有细胞静止反应，而不是凋亡。在一项对31例EML4-ALK重排的NSCLC患者的研究中，4/5的3A变异体患者表现出部分反应，1例表现为进展性疾病（仅观察到PD）。据报道，在细胞中，3a变异体比其他变异体更稳定，对环唑替尼不敏感，对hsp90抑制无反应。
The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition.