Fig. 1. A subpart of ALK-rearranged tumors survived the ALC treatment.

a Tumor volumes in 13 patients with ALK-rearranged lung cancer receiving ALC as first-line therapy in our institution. Representative CT image of a patient (top left). Changes in tumor volumes during the ALC treatment (top right). Significance was evaluated using a one-way ANOVA followed by Dunnett’s multiple comparison test. Tumor responses in 13 patients in the first evaluation (1–2 months from treatment initiation) or at the best response (bottom). b Schematic explanation of initial survival from ALK inhibitors. ALK inhibitors exert specific effects on ALK-rearranged tumors; however, some tumor cells survive (initial survival) this treatment. During months-years of treatment, tumors eventually relapsed with acquired resistance to ALK inhibitors. A waterfall plot of the changes in tumor diameter based on RECIST guideline are shown in Supplementary Fig. 1a. c Schematic explanation of the establishment of patient-derived cell lines. d–e Some ALK-rearranged NSCLC cells survived the ALC treatment; however, their proliferation was significantly suppressed under the ALC treatment in vitro. Proliferation tests (d) and initial survival rates (e) of KTOR1 and H2228 cells exposed to stepwise concentrations of ALC or DMSO (n = 6 independent experiments). Significance was evaluated using a one-way ANOVA followed by Dunnett’s multiple comparison test. The survival rate was calculated using the formula: (Cell number at 96 h)/(Cell number at 0 h = baseline) × 100. Relative cell growth was calculated by (survival rate)-100. The positive columns indicate increased cell numbers during the 96-h treatment and negative columns indicate decreased cell numbers. The results for traced experiments in KTOR2 and KTOR3 were presented in Supplementary Fig. 1b, c. CR complete response, PR partial response, SD stable disease, ALK anaplastic lymphoma kinase, NSCLC non-small cell lung cancer, ALC alectinib, DMSO dimethyl sulfoxide. Error bars indicate ± S.D. *P < 0.05.