The second-in-class proteasome inhibitor (PI) carfilzomib (Kyprolis, Cfz) has contributed to a substantial advancement in multiple myeloma treatment by improving patient survival and quality of life. A considerable portion of patients however display intrinsic resistance to Cfz. Our mechanistic understanding of intrinsic Cfz resistance is limited due to a lack of suitable cell-based models. We report that H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). These results indicate that H727 cells remain dependent on the UPS for cell survival and growth despite harboring intrinsic resistance to Cfz. Alterations in the composition of proteasome catalytic subunits via interferon-γ treatment or siRNA knockdown results in sensitization of H727 cells to Cfz. We postulate that a potential link may exist between the composition of proteasome catalytic subunits and the cellular response to Cfz. Overall, H727 cells may serve as a useful cell-based model for de novo Cfz resistance and our results suggest previously unexplored mechanisms of de novo PI resistance.
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We would like to thank the National Institutes of Health (R01 CA188354 to K.B.K.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (No. 1520250 to W.L.) and Creative-Pioneering Researchers Program through Seoul National University (to W.L.) for financially supporting this work.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-40635-1.
Lee, Min Jae; Miller, Zachary; Park, Ji Eun; Bhattarai, Deepak; Lee, Wooin; and Kim, Kyung Bo, "H727 Cells Are Inherently Resistant to the Proteasome Inhibitor Carfilzomib, Yet Require Proteasome Activity for Cell Survival and Growth" (2019). Pharmaceutical Sciences Faculty Publications. 140.