In different two-dimensional (2D) tumor cell systems, sustained ER stress by misfolded or unfolded protein accumulation in the ER induces the PERK/ATF4/CHOP/TRAIL-R2/DR5-dependent and TRAIL-independent intracellular DISC assembly that activates a caspase-8-mediated apoptotic pathway [5–7]. The gene discussed is CASP8; the disease is neoplasm.