Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

被引：342

作者：

Grommes, Christian ^{[1
,2
,3
]}

Pastore, Alessandro ^{[4
]}

Palaskas, Nicolaos ^{[2
,18
]}

Tang, Sarah S. ^{[2
]}

Campos, Carl ^{[2
]}

Schartz, Derrek ^{[2
]}

Codega, Paolo ^{[2
]}

Nichol, Donna ^{[2
,19
]}

Clark, Owen ^{[2
]}

Hsieh, Wan-Ying ^{[2
]}

Rohle, Dan ^{[2
,20
]}

Rosenblum, Marc ^{[5
]}

Viale, Agnes ^{[6
]}

Tabar, Viviane S. ^{[7
]}

Brennan, Cameron W. ^{[7
]}

Gavrilovic, Igor T. ^{[1
,3
]}

Kaley, Thomas J. ^{[1
,3
]}

Nolan, Craig P. ^{[1
,3
]}

Omuro, Antonio ^{[1
,3
,21
]}

Pentsova, Elena ^{[1
,3
]}

Thomas, Alissa A. ^{[1
,22
]}

Tsyvkin, Elina ^{[8
,9
]}

Noy, Ariela ^{[8
,9
]}

Palomba, M. Lia ^{[8
,9
]}

Hamlin, Paul ^{[8
,9
]}

Sauter, Craig S. ^{[8
,9
]}

Moskowitz, Craig H. ^{[8
,9
]}

Wolfe, Julia ^{[1
]}

Dogan, Ahmet ^{[5
]}

Won, Minhee ^{[10
]}

Glass, Jon ^{[11
]}

Peak, Scott ^{[12
]}

Lallana, Enrico C. ^{[13
]}

Hatzoglou, Vaios ^{[14
]}

Reiner, Anne S. ^{[15
]}

Gutin, Philip H. ^{[7
]}

Huse, Jason T. ^{[2
,5
,23
,24
]}

Panageas, Katherine S. ^{[15
]}

Graeber, Thomas G. ^{[16
]}

Schultz, Nikolaus ^{[2
,6
,15
]}

DeAngelis, Lisa M. ^{[1
,3
]}

Mellinghoff, Ingo K. ^{[1
,2
,3
,17
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[3] Weill Cornell Med Coll, Dept Neurol, New York, NY USA

[4] Mem Sloan Kettering Canc Ctr, Dept Computat Biol Program, 1275 York Ave, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, 1275 York Ave, New York, NY 10021 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[9] Weill Cornell Med Coll, Dept Med, New York, NY USA

[10] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA

[11] Thomas Jefferson Univ, Dept Neurosurg, Philadelphia, PA 19107 USA

[12] Permanente Med Grp Inc, Dept Neurosurg, Sacramento, CA USA

[13] Permanente Med Grp Inc, Dept Neurooncol, Redwood City, CA USA

[14] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA

[15] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[16] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Crump Inst Mol Imaging, Los Angeles, CA USA

[17] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA

[18] Univ Calif Los Angeles, Div Hematol Oncol, Los Angeles, CA USA

[19] Personal Genome Diagnost, Baltimore, MD USA

[20] Roche, Basel, Switzerland

[21] Univ Miami, Dept Neurol, Miami, FL USA

[22] Univ Vermont, Dept Neurol, Burlington, VT USA

[23] MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA

[24] MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA

来源：

CANCER DISCOVERY | 2017年 / 7卷 / 09期

关键词：

B-CELL LYMPHOMA; NF-KAPPA-B; GENE-EXPRESSION; TARGETING BTK; CANCER; MUTATIONS; PI3K; GENOME; HETEROGENEITY; HYBRIDIZATION;

D O I：

10.1158/2159-8290.CD-17-0613

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1018 / 1029

页数：12

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