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

被引:24
作者
Bisping, Guido [1 ]
Wenning, Doris [1 ]
Kropff, Martin [1 ]
Gustavus, Dirk [1 ]
Mueller-Tidow, Carsten [1 ]
Stelljes, Matthias [1 ]
Munzert, Gerd [3 ]
Hilberg, Frank [4 ]
Roth, Gerald J. [3 ]
Stefanic, Martin [3 ]
Volpert, Sarah [2 ]
Mesters, Rolf M. [1 ]
Berdel, Wolfgang E. [1 ]
Kienast, Joachim [1 ]
机构
[1] Univ Munster, Dept Med Hematol & Oncol, D-48129 Munster, Germany
[2] Univ Munster, Inst Human Genet, D-48129 Munster, Germany
[3] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
[4] Boehringer Ingelheim Austria GmbH, Vienna, Austria
关键词
MULTIPLE-MYELOMA; PROTEASOME INHIBITORS; PLUS THALIDOMIDE; ELDERLY-PATIENTS; DRUG-RESISTANCE; DOWN-REGULATION; CELLS; APOPTOSIS; INTERLEUKIN-6; COMBINATION;
D O I
10.1158/1078-0432.CCR-08-1612
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 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.
引用
收藏
页码:520 / 531
页数:12
相关论文
共 50 条
[1]   Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells [J].
Altun, M ;
Galardy, PJ ;
Shringarpure, R ;
Hideshima, T ;
LeBlanc, R ;
Anderson, KC ;
Ploegh, HL ;
Kessler, BM .
CANCER RESEARCH, 2005, 65 (17) :7896-7901
[2]   Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation [J].
Avet-Loiseau, H ;
Facon, T ;
Grosbois, B ;
Magrangeas, F ;
Rapp, MJ ;
Harousseau, JL ;
Minvielle, S ;
Bataille, R .
BLOOD, 2002, 99 (06) :2185-2191
[3]   Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma [J].
Bergsagel, PL ;
Kuehl, WM .
IMMUNOLOGICAL REVIEWS, 2003, 194 (01) :96-104
[4]   Targeting receptor kinases by a novel indolinone derivative in multiple myeloma:: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups [J].
Bisping, G ;
Kropff, M ;
Wenning, D ;
Dreyer, B ;
Bessonov, S ;
Hilberg, F ;
Roth, GJ ;
Munzert, G ;
Stefanic, M ;
Stelljes, M ;
Scheffold, C ;
Müller-Tidow, C ;
Liebisch, P ;
Lang, N ;
Tchinda, J ;
Serve, HL ;
Mesters, RM ;
Berdel, WE ;
Kienast, J .
BLOOD, 2006, 107 (05) :2079-2089
[5]   Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma [J].
Bisping, G ;
Leo, R ;
Wenning, D ;
Dankbar, B ;
Padró, T ;
Kropff, M ;
Scheffold, C ;
Kröger, M ;
Mesters, RM ;
Berdel, WE ;
Kienast, J .
BLOOD, 2003, 101 (07) :2775-2783
[6]  
BISPING G, 2005, BLOOD, V106, pA112
[7]   Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside [J].
Bruno, B ;
Giaccone, L ;
Rotta, M ;
Anderson, K ;
Boccadoro, M .
LEUKEMIA, 2005, 19 (10) :1729-1738
[8]   Perspectives for combination therapy to overcome drug-resistant multiple myeloma [J].
Catley, L ;
Tai, YT ;
Chauhan, D ;
Anderson, KC .
DRUG RESISTANCE UPDATES, 2005, 8 (04) :205-218
[9]   Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism [J].
Chauhan, D ;
Pandey, P ;
Ogata, A ;
Teoh, G ;
Treon, S ;
Urashima, M ;
Kharbanda, S ;
Anderson, KC .
ONCOGENE, 1997, 15 (07) :837-843
[10]   Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B [J].
Chauhan, D ;
Uchiyama, H ;
Akbarali, Y ;
Urashima, M ;
Yamamoto, K ;
Libermann, TA ;
Anderson, KC .
BLOOD, 1996, 87 (03) :1104-1112