Fig. 3
Anticancer activities of LCL161. A LCL161 GRDSS and IC50 distribution in T1-T5 PDOs. Reference PDOs are indicated in grey. B Protein expression of IAPs analyzed with Western blotting after treatment with DMSO (−) and 200 nM LCL161 ( +) for 48 h. C Time dependent effects of 200 nM (lo) and 2000 nM (hi) LCL161 on PARP cleavage, inhibition of XIAP and c-IAP1, Caspase- 8, 7 and 3 cleavage in LCL161-resistant T1 and sensitive T3 PDOs. (D, upper panel) Pearson correlation of significantly associating genes of RIP kinase family, gene members of the TNF signaling and other apoptosis regulators with GRDSS of LCL161. (D, lower panel) Scatter plot of RIPK1 gene expression versus LCL161 drug activity in PDOs. E. Enriched “Hallmark” gene sets in T1–T5 PDOs (colored) as compared to the reference PDO lines n = 46 (grey). F Scatter plot of Pearson’s correlation coefficients (r) between the “TNFA signaling via NFKB” gene set and remaining 49 “Hallmark” gene sets analyzed in 51 PDO lineages (vertical axis) and 30 liver metastasis tissue samples (horizontal axis). Highlighted in red are the gene sets that are enriched in T1-T5 PDOs and significantly associated with LCL161 drug activity. GRDSS Growth adjusted drug sensitivity scores, IC50 the half maximal inhibitory concentration, Cmax the maximum serum concentration of a drug, kDa kilodalton, GSVA gene set variation analysis