Epigenetic drug screen of rituximab resistant cell line revealed possible treatment targets

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F18%3A00069118" target="_blank" >RIV/65269705:_____/18:00069118 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14740/18:00104992

Výsledek na webu

<a href="http://www.ccsss.cz/index.php/ccsss/issue/viewIssue/12/22" target="_blank" >http://www.ccsss.cz/index.php/ccsss/issue/viewIssue/12/22</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Epigenetic drug screen of rituximab resistant cell line revealed possible treatment targets

Popis výsledku v původním jazyce

Standard of care for B-lymphoid malignancies nowadays still relies on the administration of monoclonal antibodies, with CD20 antigen being the prime target. Although effective at first, repeated cycles of anti-CD20 monoclonal antibody therapy often result in the loss of CD20 on the surface of malignant B cells and consequently in therapy resistance and therapy failure1,2. We mimicked the situation in patients through chronic exposure of B-lymphoid cell lines to gradually increasing doses of anti-CD20 antibody Rituximab. In this way, we have generated cell lines that are resistant to additional treatment with anti-CD20 antibodies. We could confirm that these resistant cells have downregulated CD20 protein from the cell surface. Interestingly, Rituximab was suggested to induce epigenetic changes within the CD20 promotor and, consequently, inhibitors of DNA methyltransferases and histone deacetylases were proposed to increase CD20 expression in some lymphoma cell lines3,4. Therefore, we have performed a screen with a library consisting of 182 small-molecule compounds targeting various epigenetic modifying enzymes (histone deacetylases, methyltransferases, etc.). We aimed to uncover which epigenetic modifiers were able to enhance the expression levels of CD20 antigen and recover its presence on the cell surface. The most significant increase of CD20 surface density was detected with JAK kinase inhibitor LY2784544. Increase of CD20 surface level was also detected repeatedly using various Aurora kinase inhibitors e.g. GSK1070916, JNJ-7706621, AMG-900 and MK-5108, which could indicate the role of these kinases in CD20 regulation. Further analysis of mechanisms regulating CD20 expression is needed in order to confirm the effect of detected inhibitors and thereby to enhance the therapeutic potential of CD20 monoclonal antibodies.

Název v anglickém jazyce

Epigenetic drug screen of rituximab resistant cell line revealed possible treatment targets

Popis výsledku anglicky

Standard of care for B-lymphoid malignancies nowadays still relies on the administration of monoclonal antibodies, with CD20 antigen being the prime target. Although effective at first, repeated cycles of anti-CD20 monoclonal antibody therapy often result in the loss of CD20 on the surface of malignant B cells and consequently in therapy resistance and therapy failure1,2. We mimicked the situation in patients through chronic exposure of B-lymphoid cell lines to gradually increasing doses of anti-CD20 antibody Rituximab. In this way, we have generated cell lines that are resistant to additional treatment with anti-CD20 antibodies. We could confirm that these resistant cells have downregulated CD20 protein from the cell surface. Interestingly, Rituximab was suggested to induce epigenetic changes within the CD20 promotor and, consequently, inhibitors of DNA methyltransferases and histone deacetylases were proposed to increase CD20 expression in some lymphoma cell lines3,4. Therefore, we have performed a screen with a library consisting of 182 small-molecule compounds targeting various epigenetic modifying enzymes (histone deacetylases, methyltransferases, etc.). We aimed to uncover which epigenetic modifiers were able to enhance the expression levels of CD20 antigen and recover its presence on the cell surface. The most significant increase of CD20 surface density was detected with JAK kinase inhibitor LY2784544. Increase of CD20 surface level was also detected repeatedly using various Aurora kinase inhibitors e.g. GSK1070916, JNJ-7706621, AMG-900 and MK-5108, which could indicate the role of these kinases in CD20 regulation. Further analysis of mechanisms regulating CD20 expression is needed in order to confirm the effect of detected inhibitors and thereby to enhance the therapeutic potential of CD20 monoclonal antibodies.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/NV15-33561A" target="_blank" >NV15-33561A: Rezistence na léčbu monoklonálními protilátkami u B-CLL a B-lymfomů: příčiny vzniku a potenciální intervenční strategie</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů