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

doi:10.19401/j.cnki.1007-3639.2022.08.009

Abstract

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 more 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 TKIs 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.

Key words: Non-small cell lung cancer, Anaplastic lymphoma kinase, Kinase domain, Mutation, Drug resistance

CLC Number:

R734.2

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.

Figures/Tables 2

Tab. 1

Previously reported drug resistant mutations spectrum in ALK kinase domain"

Mutation	Site	Resistance	Partner	Referance
G1123S	ATP-binding pocket	Crizotinib, ceritinib	EML4-ALK	[32]
G1128A	ATP-binding pocket	Crizotinib	EML4-ALK	[33]
T1151K/M	N-terminal to the αC-helix	Crizotinib, ceritinib	EML4-ALK	[34]
1151Tins	N-terminal to the αC-helix	Crizotinib, ceritinib, alectinib	EML4-ALK	[35-36]
L1152R/P	N-terminal to the αC-helix	Crizotinib, ceritinib	EML4-ALK	[37-38]
C1156Y	N-terminal to the αC-helix	Crizotinib, ceritinib	EML4-ALK	[17, 31, 39-40]
I1171T/N/S	C-terminal to the αC-helix	Crizotinib, alectinib, brigatinib	EML4-ALK	[22, 41-42]
F1174L	C-terminal to the αC-helix	Crizotinib, ceritinib	RANBP2-ALK	[17, 40, 43]
F1174V	C-terminal to the αC-helix	Crizotinib, ceritinib	EML4-ALK	[22, 40, 44]
F1174C	C-terminal to the αC-helix	Crizotinib, ceritinib	EML4-ALK	[40, 44]
F1174I	C-terminal to the αC-helix	Crizotinib, alectinib	EML4-ALK	[22]
V1180L	Gatekeeper mutation	Crizotinib, alectinib	EML4-ALK	[45-46]
L1196M	Gatekeeper mutation	Crizotinib, alectinib	EML4-ALK	[17, 22, 31, 39]
L1196Q	Gatekeeper mutation	Crizotinib, alectinib	EML4-ALK	[22, 47]
L1198F	Solvent front	Crizotinib, ceritinib, alectinib, brigatinib, lorlatinib	EML4-ALK	[22, 38, 48]
L1198P	Solvent front	Crizotinib	EML4-ALK	[43]
G1202R/del	Solvent front	Crizotinib, alectinib, ceritinib, brigatinib, ensartinib	EML4-ALK	[22, 29, 35, 40, 44]
D1203N	ATP-binding pocket	Crizotinib, ceritinib	EML4-ALK	[43]
S1206Y/R	Solvent front	Crizotinib	EML4-ALK	[17, 35]
E1210K	Ribose binding pocket	Crizotinib, ensartinib	EML4-ALK	[27, 29]
F1245C	Asp-Phe-Gly motif	Crizotinib	EML4-ALK	[49]
L1256F	ATP-binding pocket	Crizotinib, lorlatinib	EML4-ALK	[22]
I1268L	Asp-Phe-Gly motif	Crizotinib	EML4-ALK	[22]
G1269A	Asp-Phe-Gly motif	Crizotinib, ensartinib	EML4-ALK	[39]
G1269S	Asp-Phe-Gly motif	Crizotinib	EML4-ALK	[17, 43]
R1275Q	αAL-helix	Crizotinib, ceritinib	EML4-ALK	[50]

Tab. 1

Tab. 2

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