Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma Journal Article


Authors: Grommes, C.; Pastore, A.; Palaskas, N.; Tang, S. S.; Campos, C.; Schartz, D.; Codega, P.; Nichol, D.; Clark, O.; Hsieh, W. Y.; Rohle, D.; Rosenblum, M.; Viale, A.; Tabar, V. S.; Brennan, C. W.; Gavrilovic, I. T.; Kaley, T. J.; Nolan, C. P.; Omuro, A.; Pentsova, E.; Thomas, A. A.; Tsyvkin, E.; Noy, A.; Palomba, M. L.; Hamlin, P.; Sauter, C. S.; Moskowitz, C. H.; Wolfe, J.; Dogan, A.; Won, M.; Glass, J.; Peak, S.; Lallana, E. C.; Hatzoglou, V.; Reiner, A. S.; Gutin, P. H.; Huse, J. T.; Panageas, K. S.; Graeber, T. G.; Schultz, N.; DeAngelis, L. M.; Mellinghoff, I. K.
Article Title: Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma
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. © 2017 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 7
Issue: 9
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2017-09-01
Start Page: 1018
End Page: 1029
Language: English
DOI: 10.1158/2159-8290.cd-17-0613
PROVIDER: scopus
PMCID: PMC5581705
PUBMED: 28619981
DOI/URL:
Notes: Article -- Export Date: 2 October 2017 -- Source: Scopus
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MSK Authors
  1. Anne S Reiner
    140 Reiner
  2. Craig Moskowitz
    388 Moskowitz
  3. Ariela Noy
    226 Noy
  4. Viviane S Tabar
    140 Tabar
  5. Maria Lia Palomba
    166 Palomba
  6. Philip H Gutin
    161 Gutin
  7. Cameron Brennan
    165 Brennan
  8. Marc Rosenblum
    329 Rosenblum
  9. Antonio Marcilio Padula Omuro
    194 Omuro
  10. Thomas Kaley
    108 Kaley
  11. Craig Steven Sauter
    199 Sauter
  12. Christian Grommes
    70 Grommes
  13. Paul Hamlin
    186 Hamlin
  14. Katherine S Panageas
    365 Panageas
  15. Jason T Huse
    132 Huse
  16. Agnes Viale
    216 Viale
  17. Craig Nolan
    50 Nolan
  18. Nikolaus D Schultz
    263 Schultz
  19. Daniel A Rohle
    14 Rohle
  20. Carl Campos
    23 Campos
  21. Owen Richard Clark
    4 Clark
  22. Ahmet Dogan
    231 Dogan
  23. Alissa A Thomas
    16 Thomas
  24. Donna   Nichol
    2 Nichol
  25. Alessandro   Pastore
    40 Pastore
  26. Paolo Codega
    7 Codega
  27. Wan-Ying Hsieh
    5 Hsieh
  28. Julia Catherine Wolfe
    13 Wolfe
  29. Sarah Shiann Tang
    3 Tang