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. 2023 May 5;14:2601. doi: 10.1038/s41467-023-38195-0

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — a Cell viability assays at different lorlatinib concentrations of Kelly cells harboring either the single parental ALK F1174L driver mutation (red circles, solid curve) or the compound mutations F1174L/L1196M (medium red diamonds, dashed curve), or F1174L/G1202R (dark red squares, dotted curve) introduced in cis using CRISPR. b Cell viability assays at different lorlatinib concentrations of CHLA-20 neuroblastoma cells harboring either the single parental ALK R1275Q mutation (blue circles, solid curve) or the compound mutation F1174L/G1202R (dark blue squares, dotted curve). Data are plotted as the mean ± SD of three biological replicates, each performed in technical triplicate. c Comparison of in vitro inhibition of purified ALK-TKD for different F1174L-based variants. IC₅₀ values for F1174L-mutated ALK-TKD were assessed for lorlatinib (red circles, solid red curve: IC₅₀ = 2.3 ± 1.1 nM) and crizotinib (open gray circles, dashed gray curve: IC₅₀ = 40 ± 20 nM), and compared with lorlatinib IC₅₀ values for F1174L/L1196M (medium red diamonds, dashed curve: IC₅₀ = 12 ± 6.2 nM) and F1174L/G1202R (dark red squares, dotted curve: IC₅₀ = 26 ± 16 nM). d Comparison of in vitro inhibition of ALK-TKD for different R1275Q-based variants. IC₅₀ values for R1275Q-mutated ALK-TKD were assessed for lorlatinib (blue circles, solid blue curve: IC₅₀ = 2.9 ± 0.8 nM) and crizotinib (open gray circles, dashed gray curve: IC₅₀ = 38 ± 24 nM), and compared with lorlatinib IC₅₀ values for R1275Q/L1196M (medium blue diamonds, dashed curve: IC₅₀ = 8 ± 5.2 nM) and R1275Q/G1202R (dark blue squares, dotted curve: IC₅₀ = 40 ± 21 nM). e Measured K_M,ATP values for different ALK-TKD variants, with numbers tabulated in Supplementary Table 1. f Focus formation assay results for ΔD1276-R1279InsE ALK (magenta) compared with wild-type (black), F1174L (red), and R1275Q (blue). Data are plotted as the mean ± SD of three biological replicates, each performed in technical duplicate. Source data are provided as a Source Data file.