Antitumor Activities Of An Oral Selective HSP90α/β Inhibitor, TAS-116, In Combination With Bortezomib In Multiple Myeloma

Abstract

Heat-shock protein 90 (HSP90) is a molecular chaperone considered to be attractive therapeutic target in many cancers, including multiple myeloma (MM), since HSP90 inhibition triggers downregulation /degradation of numerous client proteins to trigger apoptosis. In this study, we examined the anti-MM activities of a novel and orally bioavailable HSP90α/β inhibitor TAS-116 (TAIHO PHARMACEUTICAL CO., LTD., Japan) in MM. TAS-116 triggered downregulation of known client proteins associated with significant growth inhibition in MM cell lines and patient MM, without cytotoxicity in normal peripheral blood mononuclear cells. Importantly, TAS-116 showed cytotoxicity even in 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant acute B cell leukemia cell line NALM6. TAS-116 induced cell cycle arrest, associated with downregulation of cell cycle regulatory proteins; followed by apoptosis, evidenced by increased annexin V-positive staining, as well as cleavage of caspases and PARP. Since the bone marrow (BM) microenvironment plays a crucial role in MM pathogenesis including drug resistance, we further examined the effect of TAS-116 in the presence of BM stromal cells (BMSCs). TAS-116 induced significant cytotoxicity in MM cells even in the presence of BMSCs, associated with downregulation of phospho-Akt and phospho-ERK. In addition, neither exogenous IL-6 nor IGF-1 was able to protect against TAS-116. Importantly, TAS-116 did not induce cytotoxicity in BMSCs. Our previous studies have shown that combined HSP90 inhibitor and proteasome inhibitor treatment induces synergistic MM cell death; therefore we similarly examined whether TAS-116 enhances bortezomib-induced cytotoxicity. TAS-116 enhanced bortezomib-induced cytotoxicity in MM.1S and RPMI-8226 cells, associated with decreased phospho-Akt, phospho-RelA (p65), phospho-IkBa, and phospho-IKKα/β; as well as increased CHOP and PARP cleavage. These results suggest that TAS-116 blocks bortezomib-induced canonical NF-κB pathway and augments bortezomib-induced endoplasmic reticulum (ER) stress. Finally, we examined the in vivo efficacy of TAS-116 in combination with bortezomib using a xenograft murine model of human MM. Although both monotherapy of TAS-116 and bortezomib were effective, TAS-116 in combination with bortezomib significantly enhanced growth inhibition (80%, p<0.05) and prolonged overall survival (29 vs 57 days, p<0.001). Immunohistochemical analysis of harvested human MM confirmed a significant increase in cleaved caspase-3- and TUNEL-positive cells in TAS-116 animals. These treatments were well tolerated, and no significant body weight loss of the animals was observed. Taken together, our studies show that the novel and selective HSP90α/β inhibitor TAS-116 blocks MM cell growth both in vitro and in vivo, providing the preclinical framework for clinical evaluation of this agent to improve patient outcome in MM. Disclosures: Hideshima: Acetylon Pharmaceuticals: Consultancy. Ohkubo:TAIHO PHARMACEUTICAL Co.,LTD: Employment. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Utsugi:TAIHO PHARMACEUTICAL CO.,LTD: Employment. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.