Discovery of lorlatinib-resistant I1171N, or G1202R double mutations by ENU mutagenesis and its therapeutic strategies.
(a, b) Number of clones with various I1171N double mutations in the ALK kinase domain identified as lorlatinib, or ceritinib-resistant mutations by ENU mutagenesis screening. (c) The number of clones with various G1202R double mutations in the ALK kinase domain were identified from Ba/F3 G1202R#30 clonal cells as lorlatinib-resistant mutations by ENU mutagenesis screening. (d) The number of clones with various G1202R double mutations in the ALK kinase domain, identified from Ba/F3 G1202R#43 clonal cells as lorlatinib-resistant mutations by ENU mutagenesis screening. (e) Calculated IC50 values of the lorlatinib-resistant I1171N double-mutated Ba/F3 clonal cells obtained by ENU mutagenesis screening. (f) The calculated IC50 values of the lorlatinib-resistant re-induced G1202R double-mutated Ba/F3 clonal cells These cells were treated with crizotinib, alectinib, ceritinib, brigatinib, or lorlatinib for 72 h. Results are expressed as mean ± SD.