Targeting of CK1ε is required for inhibition of 4E-BP1 phosphorylation, silencing of c-Myc translation, and likely clinical activity in aggressive lymphoma. The following drugs were used: Ide, TG, PF4800567 (PF), Cfz. (A) Western blot analysis of LY7 cells treated with vehicle control (c-), and Ide, TG, and PF at 15, 25, 50 μM for 24 hours. (B) LY7 cells stably transfected with a c-Myc–overexpressing plasmid (M+) or an EV were treated at the indicated concentrations of TG for 24 hours, then processed for Cell Titer Glo to determine viability. The parental LY7 cell without plasmid transfection (NoP) served as an additional control. The protein levels of c-Myc in these samples were demonstrated in supplemental Figure 5A. (C) LY7 cells stably expressing the bicistronic reporter described in Figure 4C were treated with the indicated drugs for 24 hours. R:F Luc ratios from the treatment groups were calculated as a percentage of the untreated control, and represented the efficiency of eIF4F cap-dependent translation regulated at the endogenous 5′ UTR of c-Myc. (D) Western blot analysis of LY7 cells treated by various singles agents and combinations for 24 hours. The numbers in the combinations indicated the drug concentrations in μM. (E) Effects of CK1ε knockdown on the combination of Ide + Cfz. LY7 cells stably expressing the CK1ε targeting shRNA (shRNA+) or the parental untransduced control cells (shRNA−) were treated as indicated for 24 hours and assessed by western blot. (F) Top panel, Response to TGR-1202 as a single agent in all 14 patients with DLBCL enrolled in a phase 1 clinical study. The results of idelalisib were extracted from the publication by Westin et al.³⁴  Bottom panel, Frequency of diarrhea in all 81 patients taking TGR-1202 in the phase 1 study. The results of idelalisib were extracted from the publication by Gopal et al.³⁵  (G) Pre- and posttreatment images of x-ray computed tomography from 2 DLBCL patients treated with TGR-1202.