No single ALK mutations confer high-level resistance to lorlatinib. No single ALK mutations confer high-level resistance to lorlatinib. A, For reference are shown previously reported IC50 values of first-, second-, and third-generation ALK inhibitors on cellular ALK phosphorylation in Ba/F3 cells expressing nonmutant or mutant EML4–ALK (adapted from ref. 12). B, Scheme of ENU mutagenesis screen using Ba/F3 cells. C, Summary of the type and number of ALK kinase domain mutations identified in the mutagenesis screen using Ba/F3 cells harboring nonmutant EML4–ALK (either variant 1 or variant 3). Numerous crizotinib-resistant clones were identified, as shown at right. In contrast, no lorlatinib-resistant clones were identified at comparable and clinically achievable drug concentrations, as shown at left. Shown are combined data from two independent experiments. Satoshi Yoda et al. Cancer Discov 2018;8:714-729 ©2018 by American Association for Cancer Research