Dasatinib Is Preferentially Active in the Activated B‑Cell Subtype of Diffuse Large B‑Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL)
is a heterogeneous disease,
and at least one-third of its patients relapse after treatment with
the current chemotherapy regimen, R-CHOP. By gene-expression profiling,
patients with DLBCL can be categorized into two clinically relevant
subtypes: activated B-cell (ABC) and germinal center B-cell (GCB)
DLBCL. Patients with the ABC subtype have a worse prognosis than those
with GCB, and the subtype is defined by chronic, over-active signaling
through the B-cell receptor and NF-κB pathways. We examined
the effects of the Src family kinase (SFK) inhibitor dasatinib in
a panel of ABC and GCB DLBCL cell lines and found that the former
are much more sensitive to dasatinib than the latter. However, using
multiplexed inhibitor bead coupled to mass spectrometry (MIB/MS) kinome
profiling and Western blot analysis, we found that both subtypes display
inhibition of the SFKs in response to dasatinib after both short-
and long-term treatment. The MIB/MS analyses revealed that several
cell-cycle kinases, including CDK4, CDK6, and the Aurora kinases,
are down-regulated by dasatinib treatment in the ABC, but not in the
GCB, subtype. The present findings have potential implications for
the clinical use of dasatinib for the treatment of ABC DLBCL, either
alone or in combination with other agents.