Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma
| العنوان: | Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma |
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| المؤلفون: | Elina Tsyvkin, Minhee Won, Nicolaos Palaskas, Katherine S. Panageas, Paolo Codega, Scott Peak, Nikolaus Schultz, I. T. Gavrilovic, Thomas G. Graeber, Ahmet Dogan, Jason T. Huse, Daniel Rohle, Craig S. Sauter, Jon Glass, Viviane Tabar, Carl Campos, Agnes Viale, Craig Nolan, Alissa A. Thomas, Ariela Noy, Derrek Schartz, Vaios Hatzoglou, Julia Wolfe, M. Lia Palomba, Anne S. Reiner, Paul A. Hamlin, Craig H. Moskowitz, Christian Grommes, Thomas Kaley, Cameron Brennan, Enrico C. Lallana, Sarah S. Tang, Lisa M. DeAngelis, Alessandro Pastore, Owen Clark, Philip H. Gutin, Elena Pentsova, Antonio M. P. Omuro, Wan-Ying Hsieh, Marc K. Rosenblum, Donna Nichol, Ingo K. Mellinghoff |
| المصدر: | Cancer Discovery. 7:1018-1029 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Lymphoma, B-Cell, Maximum Tolerated Dose, Antineoplastic Agents, Central Nervous System Neoplasms, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, hemic and lymphatic diseases, Agammaglobulinaemia Tyrosine Kinase, medicine, Humans, Bruton's tyrosine kinase, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, B cell, Aged, Aged, 80 and over, biology, Adenine, breakpoint cluster region, Middle Aged, Protein-Tyrosine Kinases, CD79B, medicine.disease, Lymphoma, CARD Signaling Adaptor Proteins, Pyrimidines, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Oncology, chemistry, Drug Resistance, Neoplasm, Guanylate Cyclase, P110δ, 030220 oncology & carcinogenesis, Ibrutinib, Mutation, Immunology, biology.protein, Cancer research, Pyrazoles, Female |
| الوصف: | 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. 940. This article is highlighted in the In This Issue feature, p. 920 |
| تدمد: | 2159-8290 2159-8274 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be2710f829da8ac54042a1734ed1d60fTest https://doi.org/10.1158/2159-8290.cd-17-0613Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....be2710f829da8ac54042a1734ed1d60f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 21598274 |
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