Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma

• Published in: Leukemia research Vol. 34; no. 5; pp. 585 - 593
• Main Authors: Hollmann, C. Annette, Tzankov, Alexandar, Martínez-Marignac, Verónica L, Baker, Kristi, Grygorczyk, Czeslawa, Grygorczyk, Ryszard, Foulkes, William, Nadeau, Jay, Dirnhofer, Stephan, Aloyz, Raquel
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2010
• Subjects: Antineoplastic Agents - pharmacology; Benzamides; Blotting, Western; Calcium; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cell Line, Tumor; Cell Separation; Dasatinib; De novo resistance; Drug Resistance, Neoplasm - genetics; Enzyme Activation; Flow Cytometry; Hematology, Oncology and Palliative Medicine; Humans; Imatinib Mesylate; Immunohistochemistry; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Microscopy, Fluorescence; Piperazines - pharmacology; Pyrimidines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; src-Family Kinases - metabolism; Thiazoles - pharmacology; Tissue Array Analysis; Dasatinib; De novo resistance; Calcium; Lymphoma
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2009.08.030

Abstract We report that 38% of primary large B-cell lymphoma (DLBCL) tested expressed active Src family kinases, which are targeted by dasatinib. The expression of active Src family of kinases (SFK) in primary DLBCL tumors correlated with unfavorable prognostic markers such as Ki67 and Mum1. Using four DLBCL cell lines we found that: (1) sensitivity to dasatinib (but not imatinib) varied 400-fold; (2) dasatinib resistance was associated with distinct signaling profiles downstream of BCR activation. In particular, although Src family kinase phosphorylation was inhibited by 100–150 nM dasatinib in all cell lines, this failed to inhibit BCR-mediated Blnk phosphorylation, calcium signaling and proliferation in a dasatinib resistant cell line.