期刊
CANCER DISCOVERY
卷 7, 期 9, 页码 1018-1029出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0613
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资金
- NIH [1R01NS080944-01, P30-CA008748]
- National Brain Tumor Society
- Geoffrey Beene Cancer Research Center
- Memorial Sloan Kettering Brain Tumor Center
- Society of Memorial Sloan Kettering Cancer Center
- American Brain Tumor Association Basic Research Fellowship Award
- Lymphoma Research Foundation Career Development Award
- Susan and Peter Solomon Divisional Fund
- Cycle for Survival Equinox Innovation Award
- MSK SPORE in Lymphoma Developmental Research Program (DRP) award [5 P50 CA 192937-02]
- Mildred-Scheel Postdoctoral Research Fellowship of the Deutsche Krebshilfe e.V. [111354]
- Robertson Foundation
- Radiation Therapy Oncology Group (RTOG) translational research program grant (TRP) [176]
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-kappa B. 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 p110a/p110d 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. (C) 2017 AACR.
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