The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia

被引：462

作者：

de Rooij, Martin F. M. ^{[1
]}

Kuil, Annemieke ^{[1
]}

Geest, Christian R. ^{[2
]}

Eldering, Eric ^{[2
]}

Chang, Betty Y. ^{[3
]}

Buggy, Joseph J. ^{[3
]}

Pals, Steven T. ^{[1
]}

Spaargaren, Marcel ^{[1
]}

机构：

[1] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, NL-1105 AZ Amsterdam, Netherlands

[3] Pharmacyclics Inc, Sunnyvale, CA USA

来源：

BLOOD | 2012年 / 119卷 / 11期

关键词：

TYROSINE KINASE; CLL; ACTIVATION;

D O I：

10.1182/blood-2011-11-390989

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin alpha(4)beta(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLLcells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth-and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression. (Blood. 2012;119(11):2590-2594)

引用

页码：2590 / 2594

页数：5

共 24 条

[1] Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia [J].

Buchner, Maike ;

Baer, Constance ;

Prinz, Gabriele ;

Dierks, Christine ;

Burger, Meike ;

Zenz, Thorsten ;

Stilgenbauer, Stephan ;

Jumaa, Hassan ;

Veelken, Hendrik ;

Zirlik, Katja .

BLOOD, 2010, 115 (22) :4497-4506

[2]

Burger J, 2010, BLOOD, V116

[3] Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): From understanding the basics towards therapeutic targeting [J].

Burger, Jan A. .

SEMINARS IN CANCER BIOLOGY, 2010, 20 (06) :424-430

[4] The microenvironment in mature B-cell malignancies: a target for new treatment strategies [J].

Burger, Jan A. ;

Ghia, Paolo ;

Rosenwald, Andreas ;

Caligaris-Cappio, Federico .

BLOOD, 2009, 114 (16) :3367-3375

[5] Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study [J].

Byrd, J. C. ;

Blum, K. A. ;

Burger, J. A. ;

Coutre, S. E. ;

Sharman, J. P. ;

Furman, R. R. ;

Flinn, I. W. ;

Grant, B. W. ;

Richards, D. A. ;

Zhao, W. ;

Heerema, N. A. ;

Johnson, A. J. ;

Izumi, R. ;

Hamdy, A. ;

O'Brien, S. M. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (15)

[6] Primary B Cell Immunodeficiencies: Comparisons and Contrasts [J].

Conley, Mary Ellen ;

Dobbs, A. Kerry ;

Farmer, Dana M. ;

Kilic, Sebnem ;

Paris, Kenneth ;

Grigoriadou, Sofia ;

Coustan-Smith, Elaine ;

Howard, Vanessa ;

Campana, Dario .

ANNUAL REVIEW OF IMMUNOLOGY, 2009, 27 :199-227

[7] The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells [J].

de Gorter, David J. J. ;

Reijmers, Rogier M. ;

Beuling, Esther A. ;

Naber, Hildegonda P. H. ;

Kuil, Annemieke ;

Kersten, Marie Jose ;

Pals, Steven T. ;

Spaargaren, Marcel .

BLOOD, 2008, 111 (07) :3364-3372

[8] Bruton's tyrosine kinase and phospholipase Cγ2 mediate chemokine-controlled B cell migration and homing [J].

de Gorter, David J. J. ;

Beuling, Esther A. ;

Kersseboom, Rogier ;

Middendorp, Sabine ;

van Gils, Janine M. ;

Hendriks, Rudolf W. ;

Pals, Steven T. ;

Spaargaren, Marcel .

IMMUNITY, 2007, 26 (01) :93-104

[9]

Fowler N, 2010, BLOOD, V116

[10] Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia [J].

Friedberg, Jonathan W. ;

Sharman, Jeff ;

Sweetenham, John ;

Johnston, Patrick B. ;

Vose, Julie M. ;

LaCasce, Ann ;

Schaefer-Cutillo, Julia ;

De Vos, Sven ;

Sinha, Rajni ;

Leonard, John P. ;

Cripe, Larry D. ;

Gregory, Stephanie A. ;

Sterba, Michael P. ;

Lowe, Ann M. ;

Levy, Ronald ;

Shipp, Margaret A. .

BLOOD, 2010, 115 (13) :2578-2585

← 1 2 3 →