Syrbactin proteasome inhibitor TIR-199 overcomes bortezomib chemoresistance and inhibits multiple myeloma tumor growth in vivo
Marquicia R. PierceReeder M. RobinsonTannya R. Ibarra‐RiveraMichael C. PirrungNathan G. DolloffAndré S. Bachmann
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Abstract Proteasome inhibitors bortezomib and carfilzomib are the backbone of treatments of multiple myeloma, which remains uncurable despite many recent advances. With many patients relapsing despite high initial response rates to proteasome inhibitor-containing regimens, it is critical to understand the process of acquired resistance. In vitro generated resistant cell lines are important tools in this process. The majority of previously developed bortezomib-resistant cell lines bear mutations in the proteasome PSMB5 sites, the prime target of bortezomib and carfilzomib, which are rarely observed in patients. Here we present a novel bortezomib-resistant derivative of KMS-12-BM multiple myeloma cell line, KMS-12-BM-BPR. Unlike previously published bortezomib-resistant cell lines, this sub-line was created using a clinically relevant twice-weekly pulse treatments with bortezomib instead of continuous incubation. It does not contain mutations in proteasome active sites and retains its sensitivity to carfilzomib. Reduced load on proteasome due to decreased protein synthesis appears to be the main cause of resistance. In addition, KMS-12-BM-BPR cells express less Mcl-1 than wild type and are more sensitive to Bcl-2 inhibitor venetoclax. Overall, this study demonstrates the feasibility of creating a proteasome-resistant myeloma cell lines by using clinically relevant pulse treatments and provides a novel model of acquired resistance.
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Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are refractory to bortezomib and immunomodulatory agents. This review focuses on the pharmacology, safety, and efficacy of carfilzomib for the treatment of multiple myeloma in bortezomib-naïve and bortezomib-exposed populations.
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Proteasome inhibitor resistance is a challenge for myeloma therapy. Bortezomib targets the β5 and β1 activity, but not the β2 activity of the proteasome. Bortezomib-resistant myeloma cells down-regulate the activation status of the unfolded protein response, and up-regulate β2 proteasome activity. To improve proteasome inhibition in bortezomib-resistant myeloma and to achieve more efficient UPR activation, we have developed LU-102, a selective inhibitor of the β2 proteasome activity. LU-102 inhibited the β2 activity in intact myeloma cells at low micromolar concentrations without relevant co-inhibition of β1 and β5 proteasome subunits. In proteasome inhibitor-resistant myeloma cells, significantly more potent proteasome inhibition was achieved by bortezomib or carfilzomib in combination with LU-102, compared to bortezomib/carfilzomib alone, resulting in highly synergistic cytotoxic activity of the drug combination via endoplasmatic reticulum stress-induced apoptosis. Combining bortezomib/carfilzomib with LU-102 significantly prolonged proteasome inhibition and increased activation of the unfolded protein response and IRE1-a activity. IRE1-α has recently been shown to control myeloma cell differentiation and bortezomib sensitivity (Leung-Hagesteijn, Cancer Cell 24:3, 289-304). Thus, β2-selective proteasome inhibition by LU-102 in combination with bortezomib or carfilzomib results in synergistic proteasome inhibition, activation of the unfolded protein response, and cytotoxicity, and overcomes bortezomib/carfilzomib resistance in myeloma cells in vitro
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Bortezomib was the first proteasome inhibitor (PI) discovered and demonstrated great efficacy in myeloma, both in vitro and in patients. However, still many patients ultimately relapse and there is the need for novel therapies. A second generation of PI have been discovered, potentially more effective ands some also orally administered. Carfilzomib is an irreversible proteasome inhibitor that showed great efficacy in clinical studies. Ixazomib is an oral compound that has been introduced recently in the therapeutic spectrum. Novel agents such as Marizomib seem promising in the fact that can also pass through the blood brain barrier and maybe effective also in CNS muyeloma. This review focus on all proteasome inhibitors available in clinics and the new ones coming soon. Keywords: Myeloma, bortezomib, new proteasome inhibitors, carfilzomib, oprozomib.
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Abstract Proteasomal inhibition has proven good clinical effect in Multiple Myeloma; however, some patients are resistant to treatment and most patients acquire resistance during the disease course. It is well known that cells degrade proteins by two distinct but interconnected pathways; one is protein degradation by proteasomes, which may be clinically targeted by proteasome inhibitors, the other is by formation of autophagosomes and lysosomal degradation, which can be inhibited by hydroxychloroquine (HCQ). Assuming that the two arms of protein degradation may compensate for each other, there is a rationale to simultaneously target both arms. We tested the combined effects of HCQ and the reversible proteasome inhibitor bortezomib or the irreversible inhibitor carfilzomib on myeloma cell lines and primary cells. As expected, HCQ potentiated carfilzomib-induced myeloma cell death, but surprisingly, HCQ had little or no effect on bortezomib activity. We also found that HCQ potentiated the effect of the irreversible proteasome inhibitor oprozomib, but not the effect of the reversible inhibitor ixazomib. Thus, the sensitivity towards the irreversible proteasome inhibitors carfilzomib or oprozomib is to a larger extent affected by the autophagic system than the reversible inhibitors bortezomib and ixazomib. In conclusion, we here suggest that in attempts to increase the clinical efficacy of proteasome inhibitors, inhibitors of autophagy and lysosomal degradation such as HCQ should be combined with an irreversible proteasome inhibitor such as carfilzomib, and not with bortezomib. Citation Format: Kristine Misund, Katarzyna Anna Baranowska, Toril Holien, Kristian Starheim, Ida Johansson, Glenn Buene, Anders Waage, Geir Bjørkøy, Anders Sundan. Chloroquine potentiates carfilzomib but not bortezomib effects on myeloma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1768. doi:10.1158/1538-7445.AM2015-1768
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