Research progress of ALK kinase domain drug resistance mutation and its future countermeasures

Liyuan HE; Yudong WANG

doi:10.19401/j.cnki.1007-3639.2022.08.009

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Research progress of ALK kinase domain drug resistance mutation and its future countermeasures

Review | 更新时间：2025-12-31

- Research progress of ALK kinase domain drug resistance mutation and its future countermeasures
- China Oncology Vol. 32, Issue 8, Pages: 736-746(2022)
- 作者机构：
  
  河北医科大学第四医院肿瘤内科,河北石家庄 050011
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.08.009
  CLC： R734.2
- Received：21 March 2022，
  
  Published：30 August 2022
- 稿件说明：
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Liyuan HE, Yudong WANG. Research progress of ALK kinase domain drug resistance mutation and its future countermeasures[J]. China Oncology, 2022, 32(8): 736-746.
DOI：

Liyuan HE, Yudong WANG. Research progress of ALK kinase domain drug resistance mutation and its future countermeasures[J]. China Oncology, 2022, 32(8): 736-746. DOI： 10.19401/j.cnki.1007-3639.2022.08.009.

摘要

间变性淋巴瘤激酶（anaplastic lymphoma kinase

ALK）是非小细胞肺癌（non-small cell lung cancer

NSCLC）中常见的致癌驱动基因之一。酪氨酸激酶抑制剂（tyrosine kinase inhibitor

TKI）在

ALK

融合基因阳性的NSCLC患者中均取得了优异的治疗效果

然而患者最终会对TKI产生耐药性。获得性的分子生物学耐药

如ALK激酶域突变、

ALK

基因扩增和旁路异常激活等

是影响ALK

NSCLC靶向治疗效果的重要因素。获得性的ALK激酶域耐药突变现已成为关注重点。随着二代基因测序技术（next-generation sequencing

NGS）的不断进步及普及

ALK-TKI的耐药突变谱逐渐清晰

并且获得性耐药可能是动态变化的。首先

第一代、第二代TKI治疗失败后继发ALK激酶域耐药性突变以单点突变为主。约20%的患者在接受克唑替尼治疗失败后出现耐药突变

以L1196M、G1269A、C1156Y和F1174L为主。第二代TKI（包括阿来替尼、塞瑞替尼、布加替尼和恩沙替尼）耐药后点突变的发生率高达50%

且类型更丰富

例如G1202R/del、F1174C/V和I1171T/N/S等。相对于克唑替尼

第二代TKI对ALK激酶具有更高的抑制效果

可覆盖大部分的

ALK

耐药突变

但G1202R/del除外。研究发现

除G1202R是最常见的第二代TKI耐药性突变外

F1174C/L和I1171N/S/T分别是塞瑞替尼和阿来替尼的主要耐药突变

G1269A和E1210K是恩沙替尼的主要耐药突变位点。其次

第二代TKI耐药后

ALK

双重突变和

#x0201c;脱靶

#x0201d;比例显著增加。第三代TKI劳拉替尼耐药后几

乎均为复合突变

并且耐药程度更高。现已发现I1171N-双重突变及G1202R-双重突变谱

其中

G1202R+L1196M双突变显示出对所有ALK-TKI的高度耐药。此外

序贯多代ALK-TKI治疗进展后

原有耐药位点发生变化

野生型的比列升高

耐药机制可能更为复杂。目前

在克唑替尼耐药后

序贯第二代/第三代TKI可抑制绝大部分耐药突变。而第二代TKI治疗进展后

可通过序贯其他第二代TKI或劳拉替尼达到抑瘤效果。对于顽固性的溶剂前沿区域突变

劳拉替尼对G1202R突变有显著的抑制效果

而对劳拉替尼耐药的L1198F突变及L1198F-双重突变对克唑替尼重新敏感。某些复合突变对第二代TKI敏感

如I1171N+L1196M和I1171N+G1269A突变

大部分复合耐药突变仍未发现有效的抑制剂。有新一代TPX-0131和NVL-655在临床前实验中以表现出优异的抑瘤效果

尤其是能够克服

ALK

复合耐药突变

但仍需要临床试验的验证。识别ALK-TKI的激酶域耐药突变谱

选择敏感且高效的TKI治疗是近年来的研究热点。本文聚焦于获得性ALK激酶域耐药机制

系统综述了

ALK

基因背景与激酶域耐药的关系和ALK-TKI激酶域耐药突变谱和治疗策略。同时

肿瘤进展后的重复活检对于识别ALK激酶域突变以及选择最有效的治疗策略至关重要。

Abstract

Anaplastic lymphoma kinase (ALK) is one of the common oncogenic driver genes in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have achieved excellent therapeutic effects in patients with

ALK

fusion positive NSCLC. However

patients will eventually develop resistance to TKIs. Acquired molecular drug resistance mechanisms

such as ALK kinase domain mutation

ALK

gene amplification and abnormal activation of bypass

are important drug resistance mechanisms affecting the effect of targeted therapy for ALK

NSCLC. Acquired ALK kinase domain resistance mutations have become the focus of attention. With the deepening and popularization of next-generation sequencing (NGS)

the drug resistance mutation spectrum of ALK TKI is becoming clearer

and acquired drug resistance may change dynamically. First

after the treatment failure of the first (G1)/second generation (G2) TKI

the secondary ALK kinase domain resistance mutation is mainly a single point mutation. About 20% of patients develop drug resistance mutations after failure of treatment with crizotinib

mainly L1196M

G1269A

C1156Y and F1174L. The incidence of point mutations following drug resistance to second-generation TKIs (including alectinib

ceritinib

brigatinib and ensartinib) is as high as 50%

and the types are m

ore abundant

such as G1202R/del

F1174C/V and I1171T/N/S. In preclinical trials

compared with crizotinib

the G2 TKI has a higher inhibitory effect on ALK kinase and can cover most ALK resistance mutations

except G1202R/del. In addition to G1202R

F1174C/L and I1171N/S/T are the main drug-resistant mutations of ceritinib and alectinib respectively

and G1269A and E1210K are the main drug-resistant mutations of ensartinib. Secondly

the proportion of ALK double mutation and "off target" increase significantly following the resistance to the G2 TKIs. Following resistance to third generation (G3) TKI lorlatinib

almost all of them are compound mutations

and the degree of resistance is higher. I1171N double mutation and G1202R double mutation spectrum have been found. Among them

G1202R+L1196M double mutation shows high resistance to all ALK TKIs. In addition

after the progress of sequential multi-generation ALK TKI treatment

the original drug resistance sites change

the ratio of wild-type is increased

and the drug resistance mechanism may be more complex. At present

sequential G2/G3 TKIs can inhibit most drug-resistant mutations after crizotinib resistance. After the treatment progress of G2 TKI

the tumor inhibition effect can be achieved by sequential use of other G2 TKI or lorlatinib. For stubbern solvent frontier region mutation

lorlatinib has a significant inhibitory effect on G1202R mutation

while the lorlatinib resistant L1198F mutation and L1198F double mutation can be resensitized to crizotinib. Some compound mutations are sensitive to G2 TKIs

such as I1171N+L1196M and I1171N+G1269A mutations. Most compound drug-resistant mutations have not found effective inhibitors. The new generation TPX-0131 and NVL-655 show excellent antitumor effect in preclinical experiments

especially can overcome ALK compound drug resistance mutation

however

they still need to be verified by clinical trials. Identifying the kinase domain resistance mutation spectrum of ALK TKI and selecting sensitive and efficient TK

Is treatment are the research hotspots in recent years. This paper focused on the mechanism of acquired ALK kinase domain resistance

and systematically summarized the relationship between

ALK

gene background and kinase domain resistance

ALK TKI kinase domain resistance mutation spectrum and treatment strategies. At the same time

repeated biopsy after tumor progression is very important for identifying ALK kinase domain mutations and selecting the most effective treatment strategy.

关键词

Keywords

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