A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML by Srila Gopal, Qing Lu, Joshua.

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A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML by Srila Gopal, Qing Lu, Joshua J. Man, Wendy Baur, Sitara P. Rao, Lev Litichevskiy, Malvina Papanastasiou, Amanda L. Creech, Katherine C. DeRuff, James Mullahoo, Adam Officer, Shawn B. Egri, Desiree Davison, Jacob D. Jaffe, and Iris Z. Jaffe BloodAdv Volume 2(14):1680-1684 July 24, 2018 © 2018 by The American Society of Hematology

Srila Gopal et al. Blood Adv 2018;2:1680-1684 © 2018 by The American Society of Hematology

HUVECs as a model for TKI-associated vascular toxicity. HUVECs as a model for TKI-associated vascular toxicity. HUVECs were treated with clinically relevant concentrations of nontoxic imatinib and compared directly to 3 toxic TKIs (dasatinib, ponatinib, and nilotinib). (A-B) Leukocyte adhesion (A) was quantified from representative images (B) of adherent fluorescently labeled U937 leukocytes. (C-D) Wound healing (C) was determined by quantifying the number of HUVECs that migrated into the scratch wound from representative images (D) after 20 hours. (E) HUVEC survival was quantified by the Cell TiterGlo Luminescent assay. Data are presented as mean fold change ± standard error of the mean relative to vehicle-treated control. Significance was determined by 1-way analysis of variance and Dunnett post-test. **P < .01; ***P < .001 vs vehicle. ###P < .001 vs imatinib. The number of experiments per condition is displayed within each bar. (B,D) Original magnification ×4. Srila Gopal et al. Blood Adv 2018;2:1680-1684 © 2018 by The American Society of Hematology

A phosphoproteomic signature of vascular toxicity predicts that bosutinib is nontoxic to human ECs in vitro. A phosphoproteomic signature of vascular toxicity predicts that bosutinib is nontoxic to human ECs in vitro. Phosphoproteomic profiling was performed on HUVECs treated with each TKI for 3 hours. (A) Marker selection was used to identify the top and bottom 10 peptides that distinguish the toxic (dasatinib, ponatinib, and nilotinib) from the nontoxic (imatinib) TKIs as ranked by signal to noise. Eleven peptides were chosen as the toxicity signature based on P < .05 and q < .25 (bold). (B) The similarity of each drug to one another based on the 11-phosphopeptide signature was calculated using averaged Pearson correlation coefficients. Bosutinib is more similar to the nontoxic TKI, imatinib. The diagonal (each drug vs itself) may be interpreted as replicate reproducibility. (C-D) Leukocyte adhesion (C) was quantified from representative images (D) of adherent fluorescently labeled U937 leukocytes. (E-F) Wound healing (E) was determined by quantifying the number of HUVECs that migrated into the scratch wound from representative images (F). (G) HUVEC survival was quantified by the Cell TiterGlo Luminescent assay. Data in panels C-F are presented as mean fold change ± standard error of the mean relative to vehicle-treated control. Significance was determined by 1-way analysis of variance and Dunnett post-test. *P < .05; ***P < .001 vs vehicle. ##P < .01; ###P < .001 vs dasatinib. The number of experiments per condition is displayed within each bar. (D,F) Original magnification ×4. DMSO, dimethyl sulfoxide. Srila Gopal et al. Blood Adv 2018;2:1680-1684 © 2018 by The American Society of Hematology