A combination of crizotinib and SHP099 overcomes TKI resistance in ALK⁺ ALCL in vivo. (A) Growth curves of tumor xenografts of PTPN1 KO JB6 cells injected subcutaneously in NSG mice treated with crizotinib (75 mg/kg daily), SHP099 (75 mg/kg daily), or a combination of both drugs. Data are represented as means ± SD; *P < .05, ***P < .001, ****P < .0001, 2-way ANOVA followed by Tukey's multiple comparisons test; n = 3 mice for control group, n = 10 mice for crizotinib treated group, n = 8 mice for SHP099-treated group, and n = 9 mice for combo group. (B) Representative immunohistochemistry for Ki-67 and cleaved caspase-3 performed on crizotinib-treated or crizotinib + SHP099–treated PTPN1 KO tumors. Scale bar, 50 μm. (C) Quantification of Ki-67 or cleaved caspase-3⁺ cells in PTPN1 KO tumors treated as in Figure 6A. Significance was determined by unpaired, 2-tailed Student t test, **P < .01, ****P < .0001. (D) Western blot analysis performed on lysates from PTPN1 KO tumors obtained from mice treated with the indicated drugs shows marked downregulation of ERK phosphorylation in the crizotinib plus SHP099 treatment. Two representative tumors for each treatment are shown.