Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells

Paulus, Aneel; Akhtar, Sharoon; Caulfield, Thomas R.; Samuel, Kelara; Yousaf, Haroon; Bashir, Yamima; Paulus, Shumail M.; Tran, Diem Hong; Hudec, Roman; Cogen, Davitte; Jiang, Jennifer; Edenfield, Brandy; Novak, Anne J.; Ansell, Stephen M.; Witzig, Thomas E.; Martin, Peter; Coleman, Morton; Roy, Vivek; Ailawadhi, Sikander; Chitta, Kasyapa S.; Linder, Stig; Chanan‐Khan, Asher

doi:10.1038/bcj.2016.93

Cited by 48 publications

(39 citation statements)

References 52 publications

(69 reference statements)

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“…Adversely, the competitive binding assay using Ub-VS showed that the analog displayed a greater specificity to USP14 rather than UCHL5 compared with b-AP15 [143]. In vivo studies on MM cells revealed that VLX1570 was more effective than b-AP15 in inhibiting tumor progression in mice [142]. As there is a strong outcome of VLX1570 in xenograft models, VLX1570 was then promoted to clinical trials.…”

Section: Vlx1570mentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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Section: Vlx1570mentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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“…Thus, the 19S DUBs have garnered increasing interest as potential drug targets in cancer therapy [111,256]. Inhibition of USP14 has been shown to be an effective method of intervention in several types of cancer, including squamous cell carcinoma [287], multiple myeloma [288], melanoma [289], Waldenström macroglobulinaemia [290,291], and colorectal cancer [249].…”

Section: Targeting 19s Deubiquitinases In Cancer Treatmentmentioning

confidence: 99%

“…However the commitment to apoptosis induced by b-AP15 is irreversible. This inhibitor has been shown to have anti-neoplastic effects in a variety of malignancies including acute lymphoblastic leukaemia, multiple myeloma, and Waldenström macroglobulinemia [323,324,291]. In addition to poly-ubiquitin accumulation, b-AP15 has also been observed to induce oxidative stress and ER stress in cancer cells.…”

Section: B-ap15 Structurementioning

confidence: 99%

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

et al. 2019

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“…To determine whether in vitro WM cell death, induced by Dara, can be recapitulated in an in vivo setting, we used our previously reported WM xenograft mouse model (Chitta et al , , ; Ailawadhi et al , ; Paulus et al , ). This model relies on implantation of RPCI‐WM1 cells, which were developed from a patient with highly drug‐resistant terminal‐stage WM, into immunocompromised mice (Drexler et al , ; Ailawadhi et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…Apoptosis was conducted as previously described (Manna et al , ; Paulus et al , ). Briefly, 5 × 10 5 cells were incubated with IgG1‐b12 (0.1 μg/ml), DMSO (0.001%), ibrutinib (1 μmol/l), Dara (0.1 μg/ml), or ibrutinib + Dara at 37°C and 5% CO 2 for 24 h. After 2 washes, cells were resuspended in 100 μl annexin V binding buffer, incubated for 5 min at room temperature for equilibration with buffer, and annexin V‐fluorescein isothiocyanate was added for 15 min at 37°C, per the manufacturer's instructions (BD Pharmingen, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

et al. 2018

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CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.

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Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells

Cited by 48 publications

References 52 publications

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

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