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Fig. 4 SPRED1 loss confers resistance to BRAF inhibition in BRAF-driven zebrafish melanoma in vivo and is associated with acquired resistance to targeted therapy in a patient with melanoma. (A) Representative pictures of zebrafish bearing BRAF/tp53 or BRAF/tp53/spred1 tumors and treated daily with 5 µM dabrafenib for 14 d. Scale bar, 1 cm. (B) Quantification of tumor size after 14 d of dabrafenib treatment relative to tumor size before treatment in zebrafish with BRAF/tp53 (n = 13) or BRAF/tp53/spred1 (n = 9) tumors. Pooled data of three independent experiments. **, P = 0.01, two-tailed t test. (C) Circos representation of chromosome 15 copy-number changes of four tumors from a patient who was treated with and responded to dabrafenib plus trametinib. The outermost layer represents the chromosomal regions of chromosome 15, and the inner heatmaps indicate copy-number changes (log2 ratio) averaged in 1-kb genomic windows (from inner to outer: baseline, DD-DP1, DD-DP2, and DD-DP3). Arrow indicates the location of SPRED1.