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
    212 Reiner
  2. Craig Moskowitz
    406 Moskowitz
  3. Ariela Noy
    333 Noy
  4. Viviane S Tabar
    206 Tabar
  5. Maria Lia Palomba
    349 Palomba
  6. Philip H Gutin
    163 Gutin
  7. Cameron Brennan
    212 Brennan
  8. Marc Rosenblum
    409 Rosenblum
  9. Antonio Marcilio Padula Omuro
    204 Omuro
  10. Thomas Kaley
    142 Kaley
  11. Craig Steven Sauter
    332 Sauter
  12. Elena Pentsova
    118 Pentsova
  13. Christian Grommes
    126 Grommes
  14. Paul Hamlin
    256 Hamlin
  15. Katherine S Panageas
    480 Panageas
  16. Jason T Huse
    143 Huse
  17. Agnes Viale
    241 Viale
  18. Craig Nolan
    57 Nolan
  19. Nikolaus D Schultz
    429 Schultz
  20. Daniel A Rohle
    14 Rohle
  21. Carl Campos
    30 Campos
  22. Owen Richard Clark
    5 Clark
  23. Ahmet Dogan
    399 Dogan
  24. Alissa A Thomas
    16 Thomas
  25. Donna   Nichol
    2 Nichol
  26. Alessandro   Pastore
    55 Pastore
  27. Paolo Codega
    8 Codega
  28. Wan-Ying Hsieh
    5 Hsieh
  29. Julia Catherine Wolfe
    14 Wolfe
  30. Sarah Shiann Tang
    3 Tang