Abstract
Authors
Tara L. Hogenson, William J. Phillips, Merih D. Toruner, Zachry S. Poshusta, Luciana L. Almada, Hao Xie, Ryan M. Carr, Jenny J. Li, David L. Marks, Renzo E. Vera, Erik Jessen, Michael T. Barrett, Joleen M. Hubbard, Travis E. Grotz, Martin E. Fernandez-Zapico
Figure 1
Treatment with an IGF1R inhibitor sensitizes IGF2-overexpressing CPM PDOs to doxorubicin.
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(A ) Dot plot of doxorubicin area under the curve (AUC) for 11 CPM PDOs (derived from Supplemental Figure 2A ). (B ) Z -score heatmap of AUC for 11 CPM PDOs treated with doxorubicin, MMC, and oxaliplatin (higher Z -score = resistant). (C ) Binding and Expression Target Analysis (BETA) of RNA-seq and ATAC-seq identifying top transcriptional targets in patient 6 CPM PDOs (–log10[rank product]). (D ) ATAC-seq and RNA-seq signals at the IGF2 locus; dashed lines indicate regions of significantly increased chromatin accessibility in patient 6 CPM PDOs (DiffBind). (E ) Dot plot of linsitinib AUC for 4 CPM PDOs (derived from linsitinib response in G ). (F ) Bright-field images of 4 CPM PDOs treated with vehicle (control), doxorubicin (50 nM), linsitinib (50 nM), or a combination at 6 days. Scale bar: 250 μm. (G ) Percentage viability of 4 CPM PDOs treated with doxorubicin (50 nM fixed), linsitinib (10, 50, 100 nM), or a combination. (H ) Highest Single Agent (HSA) heatmap showing percentage decrease in viability (HSA minus combination). Positive values (red) indicate the combination outperformed single agent; negative values (blue) indicate HSA outperformed the combination. P values from pairwise Wilcoxon rank-sum tests versus HO178 (IGF2-low; E and H ). NS, not significant. Black dots = sample mean; dashed line = cohort mean (A and E ). Data are presented as mean ± SEM.
