Antimyeloma activity of heat shock protein-90 inhibition

被引:258
作者
Mitsiades, CS
Mitsiades, NS
McMullan, CJ
Poulaki, V
Kung, AL
Davies, FE
Morgan, G
Akiyama, M
Shringarpure, R
Munshi, NC
Richardson, PG
Hideshima, T
Chauhan, D
Gu, XS
Bailey, C
Joseph, M
Libermann, TA
Rosen, NS
Anderson, KC
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[3] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA
[4] Dana Farber Canc Inst, Dept Cell Biol, Boston, MA 02115 USA
[5] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[6] Royal Marsden Hosp, Sutton, Surrey, England
[7] Inst Canc Res, Sutton, Surrey, England
[8] Harvard Univ, Beth Israel Deaconess Med Ctr, Inst Med, Genom Ctr, Boston, MA 02215 USA
[9] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA
关键词
D O I
10.1182/blood-2005-03-1158
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappa B, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1 alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.
引用
收藏
页码:1092 / 1100
页数:9
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