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Cancer Cells with De Novo or Acquired Resistance to Carfilzomib Remain Dependent on the Proteasome for Their Survival and Growth
Author(s) -
Lee Min Jae,
Driscoll James,
Kim Kyung Bo
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1064.5
Subject(s) - carfilzomib , proteasome , bortezomib , proteasome inhibitor , cancer research , multiple myeloma , deubiquitinating enzyme , cancer , cancer cell , ubiquitin , medicine , pharmacology , biology , immunology , microbiology and biotechnology , gene , biochemistry
Although the use of proteasome inhibitors (PIs)—bortezomib (Velcade®, Btz) and carfilzomib (Kyprolis®, Cfz)—in treating patients with multiple myeloma (MM) has successfully improved clinical outcomes, a subset of PI‐naïve patients fails to respond to these inhibitors, and almost all patients who do respond eventually acquire resistance to FDA‐approved PIs. Therefore, new therapeutic agents are urgently needed for these patients. In this study, we aim to develop novel, effective PIs for treating MM patients who do not respond or who no longer respond to Cfz therapies. We found that both H727 cancer cells with de novo Cfz resistance and RPMI 8226 multiple myeloma cells with acquired Cfz resistance remain highly sensitive to PYR‐41 (ubiquitin activating enzyme E1 inhibitor), and WP‐1130, P5091, and b‐AP15 (deubiquitinase inhibitors), suggesting that the ubiquitin‐proteasome system is essential to the survival of these Cfz‐resistant cancer cells. Additionally, silencing of proteasome α7 subunit, a component required for the assembly of active 20S proteasome, induced almost complete cell death, indicating that active proteasomes remain indispensable for the survival of Cfz‐resistant H727 cells. Based on these results, we tested the activities of cell‐permeable PIs with a variety of pharmacophores against Cfz‐resistant cancer cells. Among PIs we tested, P1' analogues of Cfz—UK101 and UK102—showed promising anticancer efficacies. Remarkably, UK‐101 and UK‐102 also displayed encouraging efficacies against primary MM cells that are resistant to both Btz and Cfz. In summary, we report that the proteasome remains essential to cancer cells that are resistant to Cfz, and that proteasome inhibition may still be a valid therapeutic strategy for patients who do not respond to Cfz therapy. Support or Funding Information This project is supported by a grant from NIH (R01 CA188354).