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Supplementary Material For Wang et al. Supplemental: Acquired resistance mutation in BRAF. Supplementary Material for: A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor Jiawan Wang, Zhan Yao, Philip Jonsson, Amy N. Allen, Alice Can Ran Qin, Sharmeen Uddin, Ira J. Dunkel, Mary Petriccione, Katia Manova, Sofia Haque, Marc K. Rosenblum, David J. Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas Supplementary Figures ⚫ Supplementary Figure S1: Representative H&E, phospho-ERK and FISH images of pre-dabrafenib (3) and post-dabrafenib (4) tumors. ⚫ Supplementary Figure S2: WES analysis of copy number variation in pre- and post- dabrafenib tumors. ⚫ Supplementary Figure S3: Whole copy number profiles from WES of pre- and post- treatment tumors. ⚫ Supplementary Figure S4: Homology alignment of BRAF p. L514 with residues in other tyrosine kinases. ⚫ Supplementary Figure S5: Relative frequency of BRAF variant alleles in SK-BT-DR cells determined by individual clone sequencing. ⚫ Supplementary Figure S6: BRAF V600E/L514V reduces dabrafenib sensitivity in NIH- 3T3 cells, related to Figure 2. ⚫ Supplementary Figure S7: BRAF V600E/L514V confers biochemical resistance to dabrafenib over a time course, related to Figure 2G. ⚫ Supplementary Figure S8: Comparison of IC50, IC75 and IC90 of dabrafenib against A375 cells expressing BRAF V600E and BRAF V600E/L514V, related to Figure 2H. ⚫ Supplementary Figure S9: The BRAF V600E/L514V double mutant promotes homodimerization, related to Figure 3A and B. ⚫ Supplementary Figure S10: BRAF L514V alone is hypoactive and associated with decreased ERK signaling that is not sensitive to dabrafenib. ⚫ Supplementary Figure S11: BRAF V600E/L514V is inhibited by dabrafenib in a purified kinase assay, indicating that it is not a gatekeeper mutation. ⚫ Supplementary Figure S12: Quantitation of p-MEK and p-ERK immunoblots, related to Figure 4B. ⚫ Supplementary Figure S13: Comparison of IC50, IC75 and IC90 of trametinib against A375 expressing BRAF V600E and BRAF V600E/L514V, related to Figure 4C. Wang et al. Supplemental: Acquired resistance mutation in BRAF. Supplementary Figure S14: The BRAF V600E/L514V mutant mediates resistance to dabrafenib that cannot be completely overcome by trametinib or dabrafenib plus trametinib, related to Figure 4D. Supplementary Figure S15: V5, p-MEK, total MEK immunoblots, and quantitation of p-ERK immunoblots, related to Figure 5A. Supplementary Figure S16: Novel RAF dimer inhibitors, MEK inhibitor and ERK inhibitor equipotently inhibit cell growth in BRAF V600E and V600E/L514V expressing cells. Supplementary Figure S17: Novel RAF dimer inhibitor, MEK inhibitor and ERK inhibitor equipotently inhibit ERK signaling in BRAF V600E and V600E/L514V expressing cells. Supplementary Figure S18: BGB3245 binds mutant BRAF V600E monomer and second site of V600E/L514V dimer with similar affinity. Supplementary Tables Supplementary Table S1: Mutations identified by WES of pre-dabrafenib and post- dabrafenib tumors. Supplementary Table S2: Secondary mutations associated with acquired resistance and occurring in residues homologous with L514 in BRAF. Supplementary Table S3: BRAF L514V allele frequency determined by ddPCR. Supplementary Methods Supplementary References Supplementary Figure S1. Wang et al. Supplemental H&E pERK BRAF - Cen7 A B C 3, pre-dabrafenib D E F 4, astrocytic G H I 4, sarcoma JK L 4, oligo-like Wang et al. Supplemental: Acquired resistance mutation in BRAF. Fig. S1. Representative H&E, phospho-ERK and FISH images of pre-dabrafenib (3) and post-dabrafenib (4) tumors. The post-dabrafenib tumor was comprised of three distinct histologic areas, including astrocytic, rhabdomyosarcomatous, and oligo-like, shown separately. A, D, G and J. H&E images. B, E, H and K. Representative images from immunohistochemical detection of phospho-ERK. C, F, I and L. 3-color BRAF/Cen7 fluorescence in situ hybridization (FISH) detection of BRAF. 3’ BRAF = Green; 5’ BRAF = Red. A centromeric repeat plasmid for chromosome 7 served as the control (Blue). Scale bars = 30 μm. Supplementary Figure S2. Wang et al. Supplemental Pre-treatment Post-treatment 2 0 (log ratio) -2 Copy number 4 2 0 -2 Allele-specific -4 (log odds ratio) 3 2 1 Integer 0 copy number 6 7 8 9 6 7 8 9 Supplementary Figure S3. Pre-treatment 2 0 -2 (log ratio) Copy number -4 Post-treatment 2 0 -2 (log ratio) Copy number -4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 171819202122 Supplementary Figure S4. 514 BRAF 500 NEVGVLR-KTRHVNILLFMGYSTKPQLA-IVTQWCEGSSLYHHLHIIE------------ 545 299 315 317 ABL1 285 KEAAVMK-EIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNR----------- 332 1180 1196 1202 1203 ALK 1166 MEALIIS-KFNHQNIVRCIGVSLQSLPRFILLELMAGGDLKSFLRETRPRP--------- 1215 783 798 ERBB2 769 DEAYVMA-GVGSPYVSRLLGICLTSTVQ-LVTQLMPYGCLLDHVRENR------------ 814 654 670 KIT 639 SELKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHA 698 573 589 595 NTRK1 559 REAELLT-MLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRFLRSHGPDAKLLA----- 612 Supplementary Figure S5. 50 40% 40 35% BRAF 30 25% 20 10 Allele frequency of 0 0 WT BRAF BRAF BRAF BRAF V600E L514V V600E L514V Wang et al. Supplemental: Acquired resistance mutation in BRAF. Fig. S2. WES analysis of copy number variation in pre- and post-dabrafenib tumors. Total, allele-specific, and integer copy number data (top, middle, and bottom) from pre- and post-treatment WES data as indicated (left and right, respectively), showing chromosomes 6-9. The BRAF locus is indicated with a green line. Fig. S3. Whole copy number profiles from WES of pre- and post- treatment tumors. Total copy number data from pre- (top) and post- (bottom) treatment tumors, showing chromosomes 1 – 22. Fig. S4. Homology alignment of BRAF p. L514 with residues in other tyrosine kinases. Alignment of the relevant BRAF sequence with that of five other tyrosine kinase targets in which secondary mutations occur as major mechanisms of acquired resistance. L514 is homologous to the amino acid changes associated with acquired resistance as shown. References: ABL1: (5-7); ALK: (8); ErbB2: (9); KIT: (10-12); NTRK1: (13, 14). Fig. S5. Relative frequency of BRAF variant alleles in SK-BT-DR cells determined by individual clone sequencing. Twenty individual clones were sequenced. The frequency of wild-type BRAF and variant alleles (V600E, L514V, or V600E/L514V) is shown as a percent of total. Supplementary Figure S6. Supplementary Figure S7. Wang et al. Supplemental GFP NIH-3T3 120 VE UT VE VELV VELV 100 - + - + - + dabrafenib BRAF 80 V5 60 pMEK 40 pERK relative pERK (%) 20 ERK 0 0 2 4 6 8 10 12 14 Time (hr) Supplementary Figure S8. dabrafenib, nM Cell line IC50 IC75 IC90 A375_VE 0.99 11.21 127.07 A375_VELV 9.52 89.66 844.08 Supplementary Figure S9. A. B. + lapatinib + - + - + - VE-V5 + - + - + - VE-FLAG - + - + - + VELV-V5 - + - + - + VELV-FLAG WT-V5/FLAG p61 VE-V5/FLAG VE-V5/FLAG VELV-V5/FLAG DMSO UT M UT M UT M 2.5 * FLAG FLAG 2.0 V5 V5 IP: Anti-V5 IP: IP: Anti-V5 IP: 1.5 BRAF FLAG FLAG 1.0 IC90 V5 V5 0.5 pMEK Cell line Input Input pMEK MEK1 Relative FLAG (IP/WCL) pERK 0 pERK MEK1 VE VELV ERK Supplementary Figure S10. A. B. BRAF BRAF VE BRAF LV BRAF VELV BRAF VELVH Vector BRAF BRAF VE BRAF VEH BRAF LV BRAF LVH BRAF VELV BRAF VELVH - + - + - + - + - + dabrafenib BRAF BRAF V5 V5 pMEK pMEK pERK pERK ERK ERK Supplementary Figure S11. 0 1 3 10 30 100 300 1000 0 1 3 10 30 100 300 1000 dabrafenib + + + + + + + + + + + + + + + + ATP BRAF pMEK MEK1 VE VELV Wang et al. Supplemental: Acquired resistance mutation in BRAF. Fig. S6. BRAF V600E/L514V reduces dabrafenib sensitivity in NIH-3T3 cells, related to Figure 2. NIH-3T3 cells were transfected with BRAF mutants (V600E or V600E/L514V) for 24 hr, followed by treatment with dabrafenib (300 nM, or DMSO as control) for 1 hr. Untransfected (UT). The indicated proteins were assessed by immunoblot. Fig. S7. BRAF V600E/L514V confers biochemical resistance to dabrafenib over a time course, related to Figure 2G. A375 cells expressing doxycycline-inducible BRAF V600E or BRAF V600E/ L514V (or GFP as control) were treated with dabrafenib (100nM) over a time course as shown. Phospho-ERK (p-ERK) (detected by immunoblot, Figure 2G) was quantitated by densitometry using Image J, and is shown as a percent of baseline (time = 0 hr) as a function of time. Fig. S8. Comparison of IC50, IC75 and IC90 of dabrafenib against A375 cells expressing BRAF V600E and BRAF V600E/L514V, related to Figure 2H. IC50, IC75 and IC90 values were calculated by CompuSyn software. Fig. S9. The BRAF V600E/L514V double mutant promotes homodimerization, related to Figure 3A and B. SKBR3 cells expressing WT BRAF and indicated tagged BRAF mutants were treated with DMSO (A) or lapatinib (B) for 1 hr. The interaction between V5-tagged and FLAG-tagged BRAF mutants were determined by immunoprecipitation (IP), followed by immunoblotting for the indicated proteins. Untransfected (UT); Whole cell lysate (WCL); Medium (M) indicates medium level of tagged construct expression, as shown in Figure 3B. Relative FLAG signal (IP/WCL) for BRAF V600E and V600E/L514V mutants in S9A was quantitated by Image J and shown as bar graph with statistical analysis to indicate replicate experiments. Wang et al. Supplemental: Acquired resistance mutation in BRAF. Fig. S10. BRAF L514V alone is hypoactive and associated with decreased ERK signaling that is not sensitive to dabrafenib. A-B. SKBR3 cells transiently transfected with the indicated plasmids were treated with lapatinib (1 μM) for 1 hr (A and B) and then treated with dabrafenib (200nM) for 1 hr (B only). Proteins as indicated were detected by immunoblotting. BRAF V600E (VE); V600E/R509H (VEH); L514V (LV); L514V/R509H (LVH); V600E/L514V (VELV); V600E/L514V/R509H (VELVH). Fig. S11. BRAF V600E/L514V is inhibited by dabrafenib in a purified kinase assay, indicating that it is not a gatekeeper mutation. 293H cells expressing V5-tagged BRAF V600E or V600E L514V were treated with dabrafenib, doses as shown.
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