Antimyeloma activity of heat shock protein-90 inhibition.
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-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha 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.
Mitsiades
Constantine S
CS
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston MA 02115, USA. constantine_mitsiades@dfci.harvard.edu
Mitsiades
Nicholas S
NS
McMullan
Ciaran J
CJ
Poulaki
Vassiliki
V
Kung
Andrew L
AL
Davies
Faith E
FE
Morgan
Gareth
G
Akiyama
Masaharu
M
Shringarpure
Reshma
R
Munshi
Nikhil C
NC
Richardson
Paul G
PG
Hideshima
Teru
T
Chauhan
Dharminder
D
Gu
Xuesong
X
Bailey
Charles
C
Joseph
Marie
M
Libermann
Towia A
TA
Rosen
Neal S
NS
Anderson
Kenneth C
KC
D000728:Androgens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D004357:Drug Synergism; D004967:Estrogens / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D047029:Lactams, Macrocyclic; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D048490:raf Kinases / Q000378:metabolism
D000728:Androgens; D000970:Antineoplastic Agents; D016227:Benzoquinones; D001897:Boronic Acids; D000069286:Bortezomib; D004967:Estrogens; D016044:Fusion Proteins, bcr-abl; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051550:I-kappa B Kinase; D047029:Lactams, Macrocyclic; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D019947:Receptors, Interleukin-6; D017828:Rifabutin; D048490:raf Kinases; C497442:HIF1A protein, human; C112765:tanespimycin