Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.
Cancer Discov
; 7(9): 1018-1029, 2017 09.
Article
em En
| MEDLINE
| ID: mdl-28619981
ABSTRACT
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance:
Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.
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Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Pirimidinas
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Linfoma de Células B
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Neoplasias do Sistema Nervoso Central
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Inibidores de Proteínas Quinases
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Antineoplásicos
Limite:
Aged80
Idioma:
En
Revista:
Cancer Discov
Ano de publicação:
2017
Tipo de documento:
Article