Figure 4.
SCD1 inhibitor induced ER stress and the UPR response in ATC cells. A, Proposed mechanism of combination therapy: A939572- or MF-438-mediated activation of the UPR through SCD1 inhibition prompts selective translation of ER stress response genes that drive prosurvival responses including decreased translation, ERAD, and chaperone-mediated protein refolding (highlighted in the green boxes). Targeted inhibition of ERAD using proteasome inhibitors such as bortezomib or carfilzomib is thought to further induce cellular stress, resulting in tumor cell apoptosis (red box). B, Monotherapeutic dose response of carfilzomib in ATC cells. IC50 values are listed. Combinatorial dose response of carfilzomib with A939572 (C) or MF-438 (E) in THJ29T and THJ16T cells are shown. D and F, Combination index values evaluating drug synergy generated using CalcuSyn software as described in the text in THJ29T and THJ16T cells. Car, carfilzomib; CI, combination index.