BRAF inhibitor-resistant BRAF-mutant melanoma cells show increased invasion and metastatic potential. BRAF inhibitor-resistant BRAF-mutant melanoma cells.

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BRAF inhibitor-resistant BRAF-mutant melanoma cells show increased invasion and metastatic potential. BRAF inhibitor-resistant BRAF-mutant melanoma cells show increased invasion and metastatic potential. A, in vitro invasion of A375, A375/R, A375(X), A375(X)/R, Colo829, and Colo829/R cells into collagen I matrices. Data are representative of 3 independent experiments, with error bars to indicate SE. *, P < 0.05; **, P < 0.01; ***, P < 0.001. B, protein interaction network showing 91 differentially expressed phosphoproteins from the cytoskeleton cluster in A375 and A375/R cells. The network was generated using STRING (23). Color coding is used to show evidence for the types of interactions between the individual phospho-proteins. C, quantification of the tumor area in the lungs of mice following tail vein injection with A375(X) or A375(X)/R cells. D, invasion of A375/R, A375(X)/R, and Colo829/R cells in the presence of DMSO, gefitinib (2 μmol/L), and dasatinib (10 nmol/L). Data are representative of 3 replicates from 3 independent experiments, with error bars to indicate SE. *, P < 0.05; **, P < 0.01. E, invasion of A375/R, A375(X)/R, and Colo829/R cells transfected with scrambled control (SC), SRC (siSRC), or LYN (siLYN) siRNA. Data are representative of 3 replicates from 3 independent experiments, with error bars to indicate SE. *, P < 0.05; **, P < 0.01. Western blots show SRC and LYN expression. Tubulin: loading control. F, quantitation of phospho-array data for STAT family members in Fig. 2A. G, Western blot analyses for phosphorylated STAT3 (pSTAT3) and STAT3 (loading control) in A375, A375/R, A375(X), A375(X)/R, Colo829, and Colo829/R cells. H, Western blot analyses for phosphorylated STAT3 (pSTAT3) and STAT3 (loading control) in A375(X)/R cells treated with DMSO, gefitinib (GEF; 2 μmol/L), dasatinib (DAS; 10 nmol/L), the JAK3 inhibitor P6 (JAK3i; 2 μmol/L), PLX4720 (PLX; 2 μmol/L), and S3I-201 (20 μmol/L). I, A375/R cell invasion in the presence of DMSO or S3I-201 (50 μmol/L). Data are representative of 3 independent experiments, with error bars to indicate SE. *, P < 0.05; **, P < 0.01. Maria R. Girotti et al. Cancer Discovery 2013;3:158-167 ©2013 by American Association for Cancer Research