pevonedistat and Multiple-Myeloma

Multiple myeloma is currently incurable, and the incidence rate is increasing year by year worldwide. Although in recent years the combined treatment plan based on proteasome inhibitors and immunomodulatory drugs has greatly improved the treatment effect of multiple myeloma, most patients still relapse and become resistant to current treatments. To solve this problem, scientists are committed to developing drugs with higher specificity, such as iberdomide, which is highly specific to ikaros and aiolos. This review aims to focus on the small molecular agents that are being researched/clinically used for the treatment of multiple myeloma, including the target mechanism, structure-activity relationship and application prospects of small molecular agents.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Combined Modality Therapy; Deubiquitinating Enzymes; Drug Development; Drug Resistance; Histone Deacetylases; Humans; Ikaros Transcription Factor; Immunomodulating Agents; Models, Molecular; Morpholines; Multiple Myeloma; Phthalimides; Piperidones; Proteasome Inhibitors; Treatment Outcome; Ubiquitin-Protein Ligases

Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma.. Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.. Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.. Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Cyclopentanes; Drug Administration Schedule; Drug Monitoring; Drug Resistance, Neoplasm; Female; Humans; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Molecular Targeted Therapy; Multiple Myeloma; NEDD8 Protein; Neoplasm Recurrence, Local; Pyrimidines; Retreatment; Treatment Outcome; Ubiquitins

Multiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.

Topics: Aged; Aged, 80 and over; Cell Degranulation; Cell Line, Tumor; Cyclopentanes; Female; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class I; Humans; Immunologic Factors; Immunomodulation; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural; Ligands; Male; Middle Aged; Multiple Myeloma; NEDD8 Protein; NK Cell Lectin-Like Receptor Subfamily K; Plasma Cells; Promoter Regions, Genetic; Pyrimidines; Up-Regulation

The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1

Topics: Adult; Aged; Apoptosis; Bortezomib; Cell Line, Tumor; Cell Survival; Cyclopentanes; Female; Humans; Male; Middle Aged; Multiple Myeloma; Necrosis; NF-kappa B; Oligopeptides; Pyrimidines; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Tumor Necrosis Factor-alpha; Ubiquitin-Activating Enzymes

Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Biomarkers, Tumor; Bortezomib; COP9 Signalosome Complex; CRISPR-Cas Systems; Cyclopentanes; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Ikaros Transcription Factor; Immunologic Factors; Multiple Myeloma; Peptide Hydrolases; Prognosis; Proteolysis; Pyrimidines; Tumor Cells, Cultured; Ubiquitin-Protein Ligases; Ubiquitination

CKS1B is significantly upregulated in multiple myeloma and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCF(Skp2) activation and offers a more specific approach to protein degradation inhibition than total proteasomal inhibition. The goal of this study was to evaluate whether MLN4924 is effective in high CKS1B conditions and identify mechanisms regulating drug potency.. Bortezomib and MLN4924 sensitivity was assessed through proliferation, viability, clonogenic potential, and senescence induction in cells overexpressing CKS1B. The mechanism for MLN4924 sensitivity was elucidated by immunoblot analysis of SCF(skp) substrates and confirmed by shRNA knockdown. The clinical relevance of the NEDD8 pathway was examined in gene expression profiles (GEP) derived from healthy people, patients with monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.. Cells overexpressing CKS1B were resistant to bortezomib but sensitive to MLN4924. Treatment of CKS1B-overexpressing cells with MLN4924 decreased proliferation, clonogenicity, and induced senescence. MLN4924, but not bortezomib, induced stabilization of p21 and knockdown of p21 resulted in loss of MLN4924 sensitivity. Patients with MGUS and multiple myeloma exhibited increased expression of NEDD8 pathway genes relative to normal plasma cells. Multiple myeloma patients with high NEDD8 expression were linked to bortezomib resistance in clinical trials, and had inferior outcomes.. Our data demonstrate that cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offer a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in multiple myeloma patients exhibiting elevated expression of CKS1B. Clin Cancer Res; 21(24); 5532-42. ©2015 AACR.

Topics: Antineoplastic Agents; Apoptosis; Bortezomib; CDC2-CDC28 Kinases; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Cyclopentanes; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Multiple Myeloma; NEDD8 Protein; Proteolysis; Pyrimidines; Signal Transduction; Ubiquitins

The function and survival of normal and malignant plasma cells depends on the elaborately regulated ubiquitin proteasome system. Proteasome inhibitors such as bortezomib have proved to be highly effective in the treatment of multiple myeloma (MM), and their effects are related to normal protein homeostasis which is critical for plasma cell survival. Many ubiquitin ligases are regulated by conjugation with NEDD8. Therefore, neddylation may also impact survival and proliferation of malignant plasma cells. Here, we show that MLN4924, a potent NEDD8 activating enzyme (NAE) inhibitor, induced cytotoxicity in MM cell lines, and its antitumor effect is associated with suppression of the AKT and mammalian target of rapamycin (mTOR) signaling pathways through increased expression of REDD1. Combining MLN4924 with the proteasome inhibitor bortezomib induces synergistic apoptosis in MM cell lines which can overcome the prosurvival effects of growth factors such as interleukin-6 and insulin-like growth factor-1. Altogether, our findings demonstrate an important function for REDD1 in MLN4924-induced cytotoxicity in MM and also provide a promising therapeutic combination strategy for myeloma.

Topics: Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Cyclopentanes; Humans; Multiple Myeloma; Proteasome Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazines; Pyrimidines; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors; Ubiquitin-Activating Enzymes; Up-Regulation

Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells.

Topics: Amides; Apoptosis; Blotting, Western; Cell Line; Cell Survival; Cyclopentanes; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase; Microscopy, Fluorescence; Multiple Myeloma; NF-kappa B; Nitriles; Pyrimidines; RNA, Small Interfering; Signal Transduction; Sulfones; Thiophenes