The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma

Moigne, Ronan Le; Aftab, Blake T.; Djakovic, Stevan; Dhimolea, Eugen; Valle, Eduardo; Murnane, Megan; King, Emily M.; Soriano, Ferdie; Menon, M.K.; Wu, Zhi Yong; Wong, Stephen T.C.; Lee, Grace J.; Yao, Bing; Wiita, Arun P.; Lam, Christine; Rice, Julie; Wang, Jinhai; Chesi, Marta; Bergsagel, P. Leif; Kraus, Marianne; Driessen, Christoph; Soly, Szerenke Kiss von; Yakes, F. Michael; Wustrow, David; Shawver, Laura K.; Zhou, Han Jie; Martin, Thomas G.; Wolf, Jeffrey L.; Mitsiades, Constantine S.; Anderson, Daniel J.; Rolfe, Mark

doi:10.1158/1535-7163.mct-17-0233

Cited by 91 publications

(79 citation statements)

References 38 publications

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“…This domain was recently shown to be involved in substrate unfolding during retrotranslocation (Bodnar and Rapoport, 2017a,b). In addition, CB-5083 kills multiple myeloma, colon and pancreatic cancer cells (Anderson et al, 2015;Le Moigne et al, 2017). Surprisingly, we found that the RMS13 and RMS13-R cells displayed identical CB-5083 sensitivities ( Fig.…”

Section: Autophagy Inhibition Re-sensitizes Rms13-r Cells To Mal3-101mentioning

confidence: 75%

Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells

Sannino

Guerriero

Sabnis

et al. 2018

Journal of Cell Science

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Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.

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Section: Autophagy Inhibition Re-sensitizes Rms13-r Cells To Mal3-101mentioning

confidence: 75%

Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells

Sannino

Guerriero

Sabnis

et al. 2018

Journal of Cell Science

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“…Additionally, CB-5083 inhibition is more efficacious in solid tumor models than proteasome inhibitors. Transcriptomics studies with MM cell lines indicate that the cellular response to CB-5083 is distinct from that of proteasome inhibitors, supporting the notion that targeting different components of the UPS can be beneficial for treating different diseases or disease states [195]. Interestingly, the transcription factor Nrf1 is an ERAD substrate and depends on p97 for its retrotranslocation [179].…”

Section: Vcp/p97 Inhibitionmentioning

confidence: 81%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

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“…Proteotoxic stress caused by these first-line therapeutic agents has been proposed to induce the apoptotic function of the unfolded protein response (UPR) 1 , leading to plasma cell death while largely sparing normal tissues 2,3 . However, despite the appealing simplicity of this mechanism, the canonical UPR is not always strongly induced in myeloma cells by PIs 4 and is unlikely to be the sole mode of PI cytotoxicity in MM. Indeed, many additional mechanisms of action of PIs have also been proposed, ranging from nuclear factor (NF)-κB inhibition to immune microenvironment effects to aberrant recycling of cytosolic amino acids 5,6 .…”

mentioning

confidence: 99%

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

et al. 2020

Self Cite

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Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

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The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma

Cited by 91 publications

References 38 publications

Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells

Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

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