Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma.
Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.
Raje
Noopur
N
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, VA Boston Healthcare System and Harvard Medical School, Boston, MA 02115, USA.
Kumar
Shaji
S
Hideshima
Teru
T
Ishitsuka
Kenji
K
Chauhan
Dharminder
D
Mitsiades
Constantine
C
Podar
Klaus
K
Le Gouill
Steven
S
Richardson
Paul
P
Munshi
Nikhil C
NC
Stirling
David I
DI
Antin
Joseph H
JH
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000633:toxicity*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000633:toxicity*
D000970:Antineoplastic Agents; D013792:Thalidomide; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077269:Lenalidomide; D020123:Sirolimus