Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells:(1) Akt (PI3K/Akt pathway), interleukin-6 R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), Cyclin-dependent kinase 4, 6, 9 (cell cycling) and I kappa B kinases (NF-kappa B pathway).(2) The expression of HSP90 is upregulated (2- to 10-fold) in tumor cells compared with normal cells, reflecting multiple oncogenic pathways and maintenance of homeostasis within tumor cells.(1,2) Because HSP90 inhibition triggers downregulation /degradation of client proteins and triggers apoptosis, it is considered a promising target for novel targeted therapies. Indeed HSP90 inhibitors (for example, geldanamycin analog 17-allylamino-17-demethoxy-geldanamycin (17-AAG), resorcinol derivatives, purine analogs) have shown early promising results in vitro and in vivo in solid tumors and some hematological malignancies, including multiple myeloma (MM).(3,4) However, some clinical studies have been discontinued due to adverse effects, including ocular toxicity.(3,5) Therefore, development of a next-generation less-toxic HSP90 inhibitor remains an important therapeutic goal.