A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor

被引：56

作者：

Burke, Russell T. ^{[1
]}

Meadows, Sarah ^{[2
]}

Loriaux, Marc M. ^{[1
,4
]}

Currie, Kevin S. ^{[3
]}

Mitchell, Scott A. ^{[3
]}

Maciejewski, Patricia ^{[3
]}

Clarke, Astrid S. ^{[3
]}

Dipaolo, Julie A. ^{[3
]}

Druker, Brian J. ^{[1
,5
]}

Lannutti, Brian J. ^{[2
]}

Spurgeon, Stephen E. ^{[1
,6
]}

机构：

[1] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[2] Gilead Sci Inc, Seattle, WA USA

[3] Gilead Sci Inc, Branford, CT USA

[4] Oregon Hlth & Sci Univ, Div Pathol, Portland, OR 97201 USA

[5] Howard Hughes Med Inst, Bethesda, MD 20817 USA

[6] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA

来源：

ONCOTARGET | 2014年 / 5卷 / 04期

关键词：

Chronic Lymphocytic Leukemia; B-cell receptor; signaling pathways; spleen tyrosine kinase; PI3; kinase; CELLS IN-VITRO; B-CELLS; SURVIVAL; ACTIVATION; APOPTOSIS; MICROENVIRONMENT; MIGRATION; INTEGRIN; CAL-101; DISEASE;

D O I：

10.18632/oncotarget.1484

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Agents that target B-cell receptor (BCR) signaling in lymphoid malignancies including idelalisib (GS-1101) and fostamatinib which inhibit the delta isoform of PI3 kinase (PI3Kd) and spleen tyrosine kinase (Syk) respectively have shown significant clinical activity. By disrupting B-cell signaling pathways, idelalisib treatment has been associated with a dramatic lymph node response, but eradication of disease and relapse in high risk disease remain challenges. Targeting the BCR signaling pathway with simultaneous inhibition of PI3Kd and Syk has not yet been reported. We evaluated the pre-clinical activity of idelalisib combined with the novel and selective Syk inhibitor GS-9973 in primary peripheral blood and bone marrow Chronic Lymphocytic Leukemia (CLL) samples. Both PI3Kd and Syk inhibition reduced CLL survival and in combination induced synergistic growth inhibition and further disrupted chemokine signaling at nanomolar concentrations including in bone marrow derived and poor risk samples. Simultaneous targeting of these kinases may significantly increase clinical activity.

引用

页码：908 / 915

页数：8

共 25 条

[1]

Targeting the microenvironment in chronic lymphocytic leukemia offers novel therapeutic options [J].