EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.
EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.
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DOI：
10.1002/1878-0261.13446
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发表时间：
2023-06
影响因子：
6.6
通讯作者：
中科院分区：
文献类型：
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间变性淋巴瘤激酶（ALK）可以通过不同类型的突变事件，如点突变（如神经母细胞瘤中的F1174L）和基因融合（如非小细胞肺癌（NSCLC）中的棘皮微管相关蛋白样4 (EML4)），被驱动成癌活性。EML4‐ALK变体产生于不同的断点，产生不同大小和性质的融合。最常见的变体（变体1和变体3）形成具有不同物理特性的细胞隔室。变体1中部分可能折叠错误的β -螺旋桨结构域的存在赋予了它形成的腔室固体样特性，更依赖于Hsp90的蛋白质稳定性和更高的细胞对ALK酪氨酸激酶抑制剂（TKIs）的敏感性。这些差异转化为临床，因为变体3，平均而言，恶化患者预后和增加转移风险。最新一代的ALK - TKIs对大多数EML4 - ALK融合患者有益。然而，对ALK抑制剂的耐药性可以通过EML4 - ALK融合的激酶结构域内的点突变发生，例如G1202R，从而降低抑制剂的有效性。在这里，我们讨论了EML4 - ALK变异的生物学，它们对治疗反应的影响，ALK - TKI耐药机制和潜在的联合治疗。EML4 - ALK耐药机制概述。EML4‐ALK变异体产生不同大小的蛋白质，形成细胞隔室。这驱动了癌症信号传导并促进了可以被ALK‐TKIs阻断的癌细胞存活途径。耐药途径可以瞄准靶点并降低ALK - TKIs的疗效；或偏离目标，并完全绕过对ALK活性的要求。
Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point‐mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule‐associated protein‐like 4 (EML4) in non‐small cell lung cancer (NSCLC). EML4‐ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta‐propeller domain in variant 1 confers solid‐like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK‐TKIs are beneficial for most patients with EML4‐ALK fusions. However, resistance to ALK inhibitors can occur via point‐mutations within the kinase domain of the EML4‐ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4‐ALK variants, their impact on treatment response, ALK‐TKI drug resistance mechanisms and potential combination therapies. Schematic overview of EML4‐ALK resistance mechanisms. EML4‐ALK variants generate proteins of different sizes that form cellular compartments. This drives cancer signalling and promotes cancer cell survival pathways that can be blocked with ALK‐TKIs. Resistance pathways can be on‐target and diminish the efficacy of ALK‐TKIs; or off‐target, and bypass the requirement for ALK activity altogether.
影响因子：
2.9
作者：
Kang J;Chen HJ;Zhang XC;Su J;Zhou Q;Tu HY;Wang Z;Wang BC;Zhong WZ;Yang XN;Chen ZH;Ding Y;Wu X;Wang M;Fu JG;Yang Z;Zhang X;Shao YW;Wu YL;Yang JJ
通讯作者：
Yang JJ