Journal: Cell reports

Article Title: Phosphoproteomics guides effective low-dose drug combinations against pancreatic ductal adenocarcinoma.

doi: 10.1016/j.celrep.2023.112581

Figure Lengend Snippet: Figure 7. Multiple LD combination reduces tumor growth and increases overall survival in vivo (A) On-treatment measurement of tumor growth (TG) after three weeks of Kolliphor, KI combination (KIC2, containing afatinib, ulixertinib, and uprosertib), saline, and gemcitabine (Gem). TG calculated relative to initial tumor sizes. Mean ± SEM plotted, n = 4–5 mice. Significance was determined using an unpaired, two- tailed Student’s t test. (B) Kaplan-Meier analysis of mice treated with KIC (median 37 days, 0.95 lower confidence limit [LCL] 31 days) and gemcitabine (median 39 days, 0.95 LCL 37 days) with respective controls of Kolliphor (median 15.5 days, 0.95 LCL 14 days) and saline (median 17 days, 0.95 LCL 14 days) for an 8-week period. Significance was determined using a log rank test. (C) Mice weight progression in percentage from the start of treatment, normalized to starting weight. (D and E) Ki67 immunohistochemical stainings of control and KIC-treated 053M tumors. (D) Quantified Ki67 expression area with ImageJ Color Deconvolution H DAB using four mice with bilateral tumors, with four 103 images per tumor. Mean ± SEM plotted. Significance was determined using an unpaired, two-tailed Student’s t test. (E) Representative images of Ki67 stainings of control and treated 053M mice. (F) Representative H&E 103 stainings of control and treated 053M mice. (G) Representative H&E stainings of the heart, liver, pancreas, spleen, and kidneys of control and treated 053M mice. See also Figure S15.

Article Snippet: Drugs were selected based on the generated phosphoproteomic profiles and on 135 drug–kinase relationships using GDSC, CCLE and Proteomics DB that evaluate KI selectivity of drugs.24–27 The following drugs were tested in vitro and/or in vivo: MET inhibitor crizotinib (Lc Laboratories), EGFR inhibitor afatinib (Lc Laboratories), SRC-family and multi-kinase inhibitor dasatinib (Lc Laboratories), ERK inhibitor ulixertinib (Carbosynth) and PI3K/AKT inhibitor uprosertib (MedChem Express), ABL inhibitor imatinib (MedChem Express), AXL inhibitor bemcentinib (MedChem Express, free sample), gemcitabine (MedChem Express), sunitinib (Pfizer) and apatinib (MedChem Express).

Techniques: In Vivo, Saline, Two Tailed Test, Immunohistochemical staining, Control, Expressing