Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients' outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

• Klíčová slova
• chemotherapy, drug resistance, non-Hodgkin lymphomas, targeted agents,
• MeSH
• chemorezistence * MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• nádorové biomarkery metabolismus   MeSH
• nehodgkinský lymfom * klasifikace   metabolismus   patologie   terapie   MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• záchranná terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH
• protinádorové látky MeSH

Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL in the last two decades has led to the design, testing, and approval of several innovative agents that dramatically changed the treatment landscape for MCL patients. Most importantly, the implementation of new drugs and novel treatment algorithms into clinical practice has successfully translated into improved outcomes of MCL patients not only in the clinical trials, but also in real life. This review focuses on recent advances in our understanding of the pathogenesis of MCL, and provides a brief survey of currently used treatment options with special focus on mode of action of selected innovative anti-lymphoma molecules. Finally, it outlines future perspectives of patient management with progressive shift from generally applied immunotherapy toward risk-stratified, patient-tailored protocols that would implement innovative agents and/or procedures with the ultimate goal to eradicate the lymphoma and cure the patient.

• Klíčová slova
• B-cell receptor signaling, cell cycle, mantle cell lymphoma,
• MeSH
• buněčný cyklus účinky léků   genetika   MeSH
• chemorezistence MeSH
• cílená molekulární terapie * metody   MeSH
• genetická variace MeSH
• klonální evoluce účinky léků   genetika   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   etiologie   metabolismus   mortalita   MeSH
• náchylnost k nemoci MeSH
• nádorové biomarkery antagonisté a inhibitory   MeSH
• prognóza MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• recidiva MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• receptory antigenů B-buněk MeSH

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 μM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.

• MeSH
• apoptóza účinky léků   MeSH
• cyklopentany farmakologie   terapeutické užití   MeSH
• inhibitory enzymů farmakologie   terapeutické užití   MeSH
• kaspasy metabolismus   MeSH
• knihovny malých molekul farmakologie   terapeutické užití   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   genetika   patologie   MeSH
• myši SCID MeSH
• nádorové buněčné linie MeSH
• NF-kappa B metabolismus   MeSH
• protein NEDD8 MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• pyrimidiny farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• separace buněk MeSH
• stanovení celkové genové exprese MeSH
• ubikvitiny antagonisté a inhibitory   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• cyklopentany MeSH
• inhibitory enzymů MeSH
• kaspasy MeSH
• knihovny malých molekul MeSH
• NEDD8 protein, human MeSH Prohlížeč
• NF-kappa B MeSH
• pevonedistat MeSH Prohlížeč
• protein NEDD8 MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• pyrimidiny MeSH
• rituximab MeSH
• ubikvitiny MeSH

Mantle cell lymphoma (MCL) is a chronically relapsing aggressive type of B-cell non-Hodgkin lymphoma considered incurable by currently used treatment approaches. Fludarabine is a purine analog clinically still widely used in the therapy of relapsed MCL. Molecular mechanisms of fludarabine resistance have not, however, been studied in the setting of MCL so far. We therefore derived fludarabine-resistant MCL cells (Mino/FR) and performed their detailed functional and proteomic characterization compared to the original fludarabine sensitive cells (Mino). We demonstrated that Mino/FR were highly cross-resistant to other antinucleosides (cytarabine, cladribine, gemcitabine) and to an inhibitor of Bruton tyrosine kinase (BTK) ibrutinib. Sensitivity to other types of anti-lymphoma agents was altered only mildly (methotrexate, doxorubicin, bortezomib) or remained unaffacted (cisplatin, bendamustine). The detailed proteomic analysis of Mino/FR compared to Mino cells unveiled over 300 differentially expressed proteins. Mino/FR were characterized by the marked downregulation of deoxycytidine kinase (dCK) and BTK (thus explaining the observed crossresistance to antinucleosides and ibrutinib), but also by the upregulation of several enzymes of de novo nucleotide synthesis, as well as the up-regulation of the numerous proteins of DNA repair and replication. The significant upregulation of the key antiapoptotic protein Bcl-2 in Mino/FR cells was associated with the markedly increased sensitivity of the fludarabine-resistant MCL cells to Bcl-2-specific inhibitor ABT199 compared to fludarabine-sensitive cells. Our data thus demonstrate that a detailed molecular analysis of drug-resistant tumor cells can indeed open a way to personalized therapy of resistant malignancies.

• MeSH
• chemorezistence * MeSH
• chromatografie kapalinová metody   MeSH
• izotopové značení metody   MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   metabolismus   MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buňky kultivované MeSH
• proteomika metody   MeSH
• protinádorové látky farmakologie   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• vidarabin analogy a deriváty   farmakologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fludarabine MeSH Prohlížeč
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• vidarabin MeSH