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Br J Cancer ; 123(2): 240-251, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32418995

RESUMO

BACKGROUND: High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents. METHODS: Functional enzymatic assays and patients' plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels. RESULTS: High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub. CONCLUSIONS: Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Farmacológicos/metabolismo , Glucuronosiltransferase/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Antígenos de Histocompatibilidade Menor/genética , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , NF-kappa B/genética , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Purinas/efeitos adversos , Purinas/farmacologia , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacologia , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/farmacologia
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