Bortezomib, dexamethasone, and fibroblast growth factor receptor 3-specific tyrosine kinase inhibitor in t(4;14) myeloma
| Autor: | Matthias Stelljes, Sarah Volpert, Martin Kropff, Joachim Kienast, Carsten Müller-Tidow, Guido Bisping, Frank Hilberg, Doris Wenning, Gerald Juergen Roth, Rolf M. Mesters, Martin Stefanic, Dirk Gustavus, Gerd Munzert, Wolfgang E. Berdel |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Antineoplastic Agents Hormonal medicine.drug_class Fibroblast Growth Factor 3 Antineoplastic Agents Tyrosine-kinase inhibitor Receptor tyrosine kinase Dexamethasone Translocation Genetic Bortezomib Cell Line Tumor medicine Humans Enzyme Inhibitors Protein kinase A In Situ Hybridization Fluorescence Chromosomes Human Pair 14 biology Fibroblast growth factor receptor 3 Protein-Tyrosine Kinases Boronic Acids Oncology Pyrazines Mutation Proteasome inhibitor biology.protein Cancer research Signal transduction Chromosomes Human Pair 4 Multiple Myeloma medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 15(2) |
| ISSN: | 1078-0432 |
| Popis: | 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, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH2-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. |
| Databáze: | OpenAIRE |
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