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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-?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 p110?/p110? 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. 940This article is highlighted in the In This Issue feature, p. 920.

SUBMITTER: Grommes C 

PROVIDER: S-EPMC5581705 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Grommes Christian C   Pastore Alessandro A   Palaskas Nicolaos N   Tang Sarah S SS   Campos Carl C   Schartz Derrek D   Codega Paolo P   Nichol Donna D   Clark Owen O   Hsieh Wan-Ying WY   Rohle Dan D   Rosenblum Marc M   Viale Agnes A   Tabar Viviane S VS   Brennan Cameron W CW   Gavrilovic Igor T IT   Kaley Thomas J TJ   Nolan Craig P CP   Omuro Antonio A   Pentsova Elena E   Thomas Alissa A AA   Tsyvkin Elina E   Noy Ariela A   Palomba M Lia ML   Hamlin Paul P   Sauter Craig S CS   Moskowitz Craig H CH   Wolfe Julia J   Dogan Ahmet A   Won Minhee M   Glass Jon J   Peak Scott S   Lallana Enrico C EC   Hatzoglou Vaios V   Reiner Anne S AS   Gutin Philip H PH   Huse Jason T JT   Panageas Katherine S KS   Graeber Thomas G TG   Schultz Nikolaus N   DeAngelis Lisa M LM   Mellinghoff Ingo K IK  

Cancer discovery 20170615 9


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 ha  ...[more]

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