RRC ID 74582
Author Furugaki K, Harada N, Yoshimura Y.
Title Sensitivity of eight types of ALK fusion variant to alectinib in ALK-transformed cells.
Journal Anticancer Drugs
Abstract Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non-small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assays using murine Ba/F3 cells expressing ALK variants. The kinase activity of each recombinant protein was significantly inhibited by alectinib. Intracellular ALK phosphorylation levels and its downstream signaling mediators, STAT3 and ERK, were suppressed by alectinib in each ALK variant-expressing Ba/F3 cell. Each cellular proliferation was markedly inhibited by alectinib treatment. There was no significant difference in the IC50 values between cells, with a <3.6-fold difference in responsiveness. In conclusion, these eight ALK variants had similar sensitivity to alectinib in vitro, indicating that it may not be possible to predict the response to alectinib just by determination of the ALK variant type in ALK fusion-positive NSCLCs.
Volume 33(2)
Pages 124-131
Published 2022-2-1
DOI 10.1097/CAD.0000000000001249
PII 00001813-202202000-00002
PMID 34520436
PMC PMC8734629
MeSH Anaplastic Lymphoma Kinase / drug effects* Anaplastic Lymphoma Kinase / genetics* Animals Carbazoles / pharmacology* Cell Proliferation / drug effects DNA, Circular Extracellular Signal-Regulated MAP Kinases / drug effects Humans Mice Phosphorylation / drug effects Piperidines / pharmacology* Protein Kinase Inhibitors / pharmacology* STAT3 Transcription Factor / drug effects Signal Transduction / drug effects
IF 2.26
Human and Animal Cells Ba/F3(RCB0805)