Specific Cell-Permeable Inhibitor of Proteasome Trypsin-like Sites Selectively Sensitizes Myeloma Cells to Bortezomib and Carfilzomib

Mirabella, Anne C.; Pletnev, Alexandre A.; Downey-Kopyscinski, Sondra L.; Florea, Bogdan I.; Shabaneh, Tamer B.; Britton, Matthew; Verdoes, Martijn; Filippov, Dmitri V.; Overkleeft, Herman S.; Kisselev, Alexei F.

doi:10.1016/j.chembiol.2011.02.015

Cited by 97 publications

(121 citation statements)

References 38 publications

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“…In an elegant series of experiments employing subunit‐specific reagents, Kisselev and co‐workers (Kisselev et al , 2006; Fuchs et al , 2008; Britton et al , 2009; Mirabella et al , 2011) demonstrated that: (i) inhibition of CT‐L activity alone only rescued 11–50% of degradation, adding T‐L inhibition increased this to 40–68%, while blocking all three subunits prevented protein breakdown by 73–91%; (ii) approximately half of MM cell lines tolerated 80–95% specific inhibition of CT‐L activity for 48 h with no loss of viability; and (iii) the pro‐apoptotic activity of BTZ and CFZ in MM cells (but not in normal PBMCs) was enhanced by addition of specific inhibitors of C‐L or T‐L or, most effectively, both. Consistent with the latter point, MRZ has been shown to act synergistically with BTZ in vitro and in vivo (Chauhan et al , 2008).…”

Section: Discussionmentioning

confidence: 99%

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

Levin¹,

Spencer

Harrison

et al. 2016

Br J Haematol

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SummaryProteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin‐like (CT‐L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase‐like (C‐L) and trypsin‐like (T‐L) subunits, in response to CT‐L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan‐proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once‐ or twice‐weekly MRZ dosing; 100% inhibition of CT‐L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C‐L and T‐L activities were either unaffected or increased, suggesting compensatory hyperactivation of these subunits. Importantly, this response was overcome by continued administration of MRZ, with robust inhibition of T‐L and C‐L (up to 80% and 50%, respectively) by the end of Cycle 2 and maintained thereafter. This enhanced proteasome inhibition was independent of tumour type and may underlie the clinical activity of MRZ in patients resistant to other PIs.

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Section: Discussionmentioning

confidence: 99%

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

Levin¹,

Spencer

Harrison

et al. 2016

Br J Haematol

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“…Although data from our group demonstrated that combined inhibition of β5 and LMP7 was necessary and sufficient to induce apoptosis in myeloma cells in vitro (Parlati et al , 2009), several studies have postulated a role for the other active sites of the i20S in anti‐myeloma responses. Kuhn et al (2009) have shown that LMP2‐selective inhibitors can induce myeloma cell death, and multiple reports have demonstrated synergistic tumour cell killing with carfilzomib or bortezomib and either an LMP2/β1 or MECL1/β2 selective inhibitor (Britton et al , 2009; Mirabella et al , 2011). It is possible that the simultaneous inhibition of multiple i20S subunits contributes to the potent anti‐tumour activity of carfilzomib in patients with MM, including patients that are refractory to bortezomib (Siegel et al , 2012; Vij et al , 2012a), particularly given that approximately 75% of the proteasomes in isolated myeloma cells are i20S.…”

Section: Discussionmentioning

confidence: 99%

“…Substrates for LMP2 and MECL1 are poorly defined and, similar to LLVY‐AMC, do not differentiate between immunoproteasome subunit activity and the corresponding constitutive proteasome subunits (Groettrup et al , 2010). Studies utilizing inhibitors that specifically target the caspase‐like or trypsin‐like active sites suggest that inhibition of non–CT‐L active sites alone may sensitize cancer cells to CT‐L inhibition but are not sufficient to induce cytotoxicity (Britton et al , 2009; Mirabella et al , 2011). Other assessment tools are needed to fully characterize the role of c20S and i20S active sites in the anti‐cancer activity of proteasome inhibitors.…”

mentioning

confidence: 99%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

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SummaryWhile proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

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“…Recently, a series of α',β'epoxyketone inhibitors that target the TL activities of the cCP and iCP was published [77] .…”

Section: Subunit-specific Proteasome Inhibitors and Their Therapeuticmentioning

confidence: 99%

Structural and Functional Characterization of the Immunoproteasome

Huber¹

2013

Springer Theses

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Specific Cell-Permeable Inhibitor of Proteasome Trypsin-like Sites Selectively Sensitizes Myeloma Cells to Bortezomib and Carfilzomib

Cited by 97 publications

References 38 publications

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Structural and Functional Characterization of the Immunoproteasome

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