中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (8): 736-746.doi: 10.19401/j.cnki.1007-3639.2022.08.009
收稿日期:
2022-03-21
出版日期:
2022-08-30
发布日期:
2022-09-19
通信作者:
王玉栋
E-mail:916974102@qq.com;15931166600@126.com
作者简介:
何丽媛(ORCID: 0000-0001-5389-6347),硕士,住院医师, E-mail: 916974102@qq.com
HE Liyuan()(
), WANG Yudong(
)(
)
Received:
2022-03-21
Published:
2022-08-30
Online:
2022-09-19
Contact:
WANG Yudong
E-mail:916974102@qq.com;15931166600@126.com
文章分享
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“脱靶”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。
中图分类号:
何丽媛, 王玉栋. ALK激酶域耐药突变的研究进展及未来应对策略[J]. 中国癌症杂志, 2022, 32(8): 736-746.
HE Liyuan, WANG Yudong. Research progress of ALK kinase domain drug resistance mutation and its future countermeasures[J]. China Oncology, 2022, 32(8): 736-746.
表1
既往报道中的ALK激酶域耐药突变谱"
Mutation | Site | Resistance | Partner | Referance |
---|---|---|---|---|
G1123S | ATP-binding pocket | Crizotinib, ceritinib | EML4-ALK | [ |
G1128A | ATP-binding pocket | Crizotinib | EML4-ALK | [ |
T1151K/M | N-terminal to the αC-helix | Crizotinib, ceritinib | EML4-ALK | [ |
1151Tins | N-terminal to the αC-helix | Crizotinib, ceritinib, alectinib | EML4-ALK | [ |
L1152R/P | N-terminal to the αC-helix | Crizotinib, ceritinib | EML4-ALK | [ |
C1156Y | N-terminal to the αC-helix | Crizotinib, ceritinib | EML4-ALK | [ |
I1171T/N/S | C-terminal to the αC-helix | Crizotinib, alectinib, brigatinib | EML4-ALK | [ |
F1174L | C-terminal to the αC-helix | Crizotinib, ceritinib | RANBP2-ALK | [ |
F1174V | C-terminal to the αC-helix | Crizotinib, ceritinib | EML4-ALK | [ |
F1174C | C-terminal to the αC-helix | Crizotinib, ceritinib | EML4-ALK | [ |
F1174I | C-terminal to the αC-helix | Crizotinib, alectinib | EML4-ALK | [ |
V1180L | Gatekeeper mutation | Crizotinib, alectinib | EML4-ALK | [ |
L1196M | Gatekeeper mutation | Crizotinib, alectinib | EML4-ALK | [ |
L1196Q | Gatekeeper mutation | Crizotinib, alectinib | EML4-ALK | [ |
L1198F | Solvent front | Crizotinib, ceritinib, alectinib, brigatinib, lorlatinib | EML4-ALK | [ |
L1198P | Solvent front | Crizotinib | EML4-ALK | [ |
G1202R/del | Solvent front | Crizotinib, alectinib, ceritinib, brigatinib, ensartinib | EML4-ALK | [ |
D1203N | ATP-binding pocket | Crizotinib, ceritinib | EML4-ALK | [ |
S1206Y/R | Solvent front | Crizotinib | EML4-ALK | [ |
E1210K | Ribose binding pocket | Crizotinib, ensartinib | EML4-ALK | [ |
F1245C | Asp-Phe-Gly motif | Crizotinib | EML4-ALK | [ |
L1256F | ATP-binding pocket | Crizotinib, lorlatinib | EML4-ALK | [ |
I1268L | Asp-Phe-Gly motif | Crizotinib | EML4-ALK | [ |
G1269A | Asp-Phe-Gly motif | Crizotinib, ensartinib | EML4-ALK | [ |
G1269S | Asp-Phe-Gly motif | Crizotinib | EML4-ALK | [ |
R1275Q | αAL-helix | Crizotinib, ceritinib | EML4-ALK | [ |
表2
ALK激酶域耐药突变对ALK-TKI的应答反应"
Mutation | Crizotinib | Ceritinib | Alectinib | Brigatinib | Ensartinib | Lorlatinib |
---|---|---|---|---|---|---|
G1123S | R | R | S | S | S | S |
T1151K/M | R | R | S | P | U | S |
1151Tins | R | R | R | P | U | S |
L1152R/P | R | R | P | S | S | S |
C1156Y | R | R | S | S | S | S |
I1171T/N/S | R | S | R | S | S | S |
F1174L | R | R | S | S | S | S |
F1174V | R | R | P | P | S | S |
F1174C | R | R | S | S | U | S |
F1174I | R | U | R | P | U | U |
V1180L | R | S | R | S | P | S |
L1196M | R | S | R | S | S | S |
L1196Q | R | S | R | S | U | S |
L1198F | S | R | R | R | R | R |
G1202R/del | R | R | R | R | R | S |
D1203N | R | R | S | P | U | S |
S1206Y/R | R | S | S | S | U | S |
E1210K | R | P | P | S | R | S |
F1245C | R | S | U | S | U | U |
L1256F | R | U | S | U | U | R |
G1269A | R | S | S | S | R | S |
R1275Q | R | R | S | U | U | U |
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