Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma.
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.
Hollmann
C Annette
CA
Sir Mortimer B Davis-Jewish General Hospital, Montreal Centre for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
Tzankov
Alexandar
A
Martínez-Marignac
Verónica L
VL
Baker
Kristi
K
Grygorczyk
Czeslawa
C
Grygorczyk
Ryszard
R
Foulkes
William
W
Nadeau
Jay
J
Dirnhofer
Stephan
S
Aloyz
Raquel
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D015153:Blotting, Western; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D046888:Tissue Array Analysis; D019061:src-Family Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019061:src-Family Kinases; D000069439:Dasatinib