biostudies-literatureUnknown2(1)Zhu VWLorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired <i>ALK</i> resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved <i>EML4-ALK</i> variant 3 G1202R/S1206Y double mutation in <i>cis</i> detected in a patient with <i>ALK</i>-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (<i>ALK</i> G1202R/L1196M, <i>ALK</i> G1202R/F1174C, <i>ALK</i> G1202R/l1198F, <i>ALK</i> G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALKJTO clinical and research reports100116https://www.ebi.ac.uk/biostudies/studies/S-EPMC8474455biostudies-literatureA Novel Sequentially Evolved <i>EML4-ALK</i> Variant 3 G1202R/S1206Y Double Mutation In <i>Cis</i> Confers Resistance to Lorlatinib: A Brief Report and Literature Review.PMC8474455Schrock ABNagasaka MMadison RCui JZhu VWOu SIfalseA Novel Sequentially Evolved <i>EML4-ALK</i> Variant 3 G1202R/S1206Y Double Mutation In <i>Cis</i> Confers Resistance to Lorlatinib: A Brief Report and Literature Review.Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired <i>ALK</i> resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved <i>EML4-ALK</i> variant 3 G1202R/S1206Y double mutation in <i>cis</i> detected in a patient with <i>ALK</i>-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (<i>ALK</i> G1202R/L1196M, <i>ALK</i> G1202R/F1174C, <i>ALK</i> G1202R/l1198F, <i>ALK</i> G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK2021-01-01T00:00:00Z2021 Jan2025-04-22T10:18:07.703Z2022-02-11T11:43:17.517ZS-EPMC84744553458997710.1016/j.jtocrr.2020.100116