THZ1 in combination with targeted therapy enhances cell death and hinders the establishment of drug-resistant colonies in diverse oncogene-addicted cellular.

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THZ1 in combination with targeted therapy enhances cell death and hinders the establishment of drug-resistant colonies in diverse oncogene-addicted cellular models. THZ1 in combination with targeted therapy enhances cell death and hinders the establishment of drug-resistant colonies in diverse oncogene-addicted cellular models. A, Receptor tyrosine kinase–dependent cell lines, RT112 (FGFR), PC9 (EGFR), and H3122 (ALK) were treated with DMSO, the corresponding tyrosine kinase inhibitor [TKI: BGJ398 (BGJ), erlotinib (Erlo), or crizotinib (Criz)], THZ1, or THZ1 in combination with the corresponding TKI. Colony formation was assayed by crystal violet staining at 4 weeks. DMSO was stained by 1 week. Two representative wells from a minimum of three biological replicates are shown per condition. (RT112: BGJ398 1 μmol/L, THZ1 100 nmol/L; PC9: erlotinib 1 μmol/L, THZ1 100 nmol/L; H3122: crizotinib 250 nmol/L, THZ1 50 nmol/L.) Note: Colony formation for RT112 with THZ1 at 150 nmol/L in combination with BGJ398 yielded no detectable colonies at 4 weeks (Supplementary Fig. S2f). B, Quantification of colony formation in A, shown as a percentage of the control. Mean (3 biological replicates) ± standard deviation (SD) shown (*, P < 0.05; **, < 0.005; ***, < 0.0005, two-sided t test). ND, not detectable. C, Cell death analysis with cells treated as in A by flow cytometry with Annexin V/PI staining, following 48 hours of treatment. Mean (3 biological replicates) ± SD shown (*, P < 0.05; **, < 0.005; ***, < 0.0005, two-sided t test, comparing total cell death; Annexin V+/PI− or PI+). Left, RT112; middle, PC9; right, H3122. D, KRAS-mutant cell lines A549, H23, and H1792 were treated with DMSO, trametinib (Tram), THZ1, or a combination of THZ1 and trametinib. Colony formation was assayed by crystal violet staining at 4 weeks. DMSO was stained by 1 week. Two representative wells from a minimum of three independent biological replicates are shown per condition. (A549: trametinib 200 nmol/L, THZ1 150 nmol/L; H23: trametinib 500 nmol/L, THZ1 100 nmol/L; H1792: trametinib 500 nmol/L, THZ1 500 nmol/L). E, Quantification of colony formation in D, shown as a percentage of the control. Mean (3 biological replicates) ± SD shown (*, P < 0.05; **, < 0.005; ***, < 0.0005, two-sided t test). ND, not detectable. F, Cell death analysis with cells treated as in D by flow cytometry with Annexin V/PI staining, following 48 hours of treatment. Mean (3 biological replicates) ± SD shown (*, P < 0.05; **, < 0.005; ***, < 0.0005, two-sided t test, comparing total cell death; Annexin V+/PI− or PI+). Left, A549; middle, H23; right, H1792. Note: H23 had different drug response dynamics compared with the other cell lines tested, with the cell death in the combination-treated group ensuing close to the 2-week time point. Maria Rusan et al. Cancer Discov 2018;8:59-73 ©2018 by American Association for Cancer Research