Abstract
Novel antineoplastic agents have opened perspectives to more selective treatment of multiple myeloma (MM). Targets include FGFR3 or c-maf and VEGFR1 expressed in MM subgroups carrying t(4;14)(p16.4;q32) or t(14;16)(q32;q23), respectively. The t(4;14) MM subgroup, overexpressing FGFR3, has been recently demonstrated to be sensitive to induction of apoptosis by receptor tyrosine kinase (RTK) inhibitors [
Bisping, Blood 102, 661, 2003
; Podar, Blood 103, 3474, 2004
; Trudel, Blood 105, 2941, 2005
]. The present study aimed at investigating mechanisms of enhanced anti-myeloma effects of BIBF 1000, a highly selective RTK inhibitor, blocking VEGF and FGF dependent signaling, in combination with the proteasome inhibitor bortezomib and/or dexamethasone in cytogenetically defined MM subgroups. MM cells analyzed included a panel of five t(4;14) and six t(14;16) positive myeloma cell lines as well as fourteen CD138+ sorted primary MM cells with or without t(4;14) (3/11). We found a significant, dose-dependent inhibition of proliferation and induction of apoptosis in t(4;14)+ MM lines (4/5) as well as in primary t(4;14)+ CD138+ sorted marrow derived MM cells (3/3) by incubation with the RTK inhibitor BIBF 1000. Coincubation with the proteasome inhibitor bortezomib, or dexamethasone, or their combination revealed stepwise increased apoptosis in non RAS-mutated t(4;14)+ MM (4/4). Induction of apoptosis by BIBF 1000 in t(4;14)+ cells was associated with inhibition of the phosphorylation of mitogen-activated protein kinase (MAPK p44/42). In contrast, inhibition of MAPK-phosphorylation failed and induction of apoptosis did not appear in n-RAS-mutated t(4;14)+ NCI-H929 cells. In t(14;16)+ MM cells, variable proapoptotic effects of BIBF 1000 (in 5 of 6 lines tested) were significantly enhanced by dexamethasone and/or bortezomib. Interleukin-6 partially antagonized and the pan-caspase inhibitor z-VAD almost completely reverted induced apoptosis upon exposure to these combinations. In t(14;16)+ MM.1S cells, induction of apoptosis by BIBF 1000 was associated with inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway. When combining BIBF 1000, bortezomib, and/or dexamethasone, we found a markedly higher proportion of cleaved caspase-3, caspase-8 and PARP in t(4;14) and t(14;16) MM, while caspase-9 was not activated. The data provide the rationale for clinical evaluation of a combination of this class of targeted tyrosine kinase inhibitors, proteasome inhibitors and dexamethasone in MM with focus on defined cytogenetic subgroups.Author notes
Corresponding author
2005, The American Society of Hematology
2005
