KW-2478 is a novel Hsp90 inhibitor with a new chemical structure and is under clinical investigation in multiple myeloma patients. Our previous study revealed that KW-2478 bind to N-terminal ATP/ADP pocket and thus inducing apoptosis in myeloma cells. Others have reported that bortezomib, a proteasome inhibitor, induces apoptosis of myeloma cells through increase of ER stress mediator protein such as Noxa. Since Hsp90 inhibition can also causes cellular stress, combining Hsp90 inhibitor and bortezomib may be of therapeutic benefit. In this study, we assessed the combined effect of KW-2478 with bortezomib using human myeloma cell lines. In OPM2/GFP cells, KW-2478 enhanced caspase activation of bortezomib in vitro and this effect was revealed to be mediated through synergistic induction of Noxa. Interestingly KW-2478 reduced bortezomib-induced level of another ER stress mediator, Puma in the same cells. To see if this in vitro effect is translated into in vivo setting, we evaluated combined anti-tumor activity of KW-2478 with bortezomib in s.c. inoculated NCI-H929 human myeloma model. In this model, twice weekly treatment of KW-2478 at the dose of 50 mg/kg (1/4 of MTD) showed synergistic anti-tumor effect with 1 mg/kg bortezomib, without significant body weight loss. Our previous studies showed that KW-2478 showed anti-tumor activity in bone marrow environment, the combined effect of KW-278 with bortezomib was further evaluated using an orthotopic myeloma model in which OPM2/GFP cells were i.v. inoculated. The combination of KW-2478 with bortezomib showed synergistic reduction of myeloma cells in bone marrow and this effect was reflected in a significant decrease in serum M protein level. Our results strongly suggested that combination of KW-2478 with bortezomib may exhibit the enhanced anti-tumor activity against human myeloma than bortezomib alone. Clinical study for combination of KW-2478 with bortzomib in myeloma patients is warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2636.

©2010 American Association for Cancer Research
2010