Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3–Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma

Abstract

Purpose: Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM. Experimental Design: We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone. Results: RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, downregulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stressactivated protein/c-Jun NH 2 -terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras^mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM. Conclusions: Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.

Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-catenin survival signaling pathways

“…CK1 inhibition in association with BZ was able to cause a moderately higher level of apoptosis compared to the single treatments and overcome BZ resistance in these cells. Furthermore, we have treated the UTMC2 cell line (which is reported to be BZ resistant [38]), with D4476. CK1 inactivation caused a strong dose dependent cytotoxicity in UTMC2 cells without an additive role with BZ.…”

DNA Methyltransferase Inhibition Reverses Epigenetically Embedded Phenotypes in Lung Cancer Preferentially Affecting Polycomb Target Genes

“…Proliferation assays with 3 [H]-thymidine incorporation (14), migration assays (12,14), cell viability assays (15), and human tumor cloning assays (16) were performed as described.…”

Effect of a Proteasome Inhibitor Plus Steroids on HLA Antibodies in Sensitized Patients Awaiting a Renal Transplant

“…However, they observed a reduction in antiYclass I antibodies at 3 months after a second course of bortezomib associated with dexamethasone, suggesting that bortezomib plus dexamethasone and/or a second course of bortezomib could be active on antiYHLA-secreting cells. Because bortezomib is used in combination with steroids that have a synergistic effect on plasma cells for the treatment of myeloma (25), we hypothesized that the combination of both molecules could decrease anti-HLA antibodies in immunized patients. In our study, 23 patients were desensitized with B+S before transplantation.…”