TAS‐116 (pimitespib), a heat shock protein 90 inhibitor, shows efficacy in preclinical models of adult T‐cell leukemia

Abstract

Adult T‐cell leukemia/lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T‐cell leukemia virus type 1 infection, for which there is an urgent need for more effective therapeutic options. The molecular chaperone heat shock protein 90 (HSP90) plays a crucial role in nuclear factor‐κB (NF‐κB)‐mediated antiapoptosis in ATL cells, and HSP90 inhibitors are new candidate therapeutics for ATL. Accordingly, we investigated the anti‐ATL effects of a novel oral HSP90 inhibitor, TAS‐116 (pimitespib), and the mechanisms involved in ex vivo and in vivo preclinical models. TAS‐116 achieved IC50 values of less than 0.5 μmol/L in 10 ATL‐related cell lines and less than 1 μmol/L in primary peripheral blood cells of nine ATL patients; no toxicity was observed toward CD4+ lymphocytes from healthy donors, indicating the safety of this agent. Given orally, TAS‐116 also showed significant inhibitory effects against tumor cell growth in ATL cell‐xenografted mice. Furthermore, gene expression profiling of TAS‐116‐treated Tax‐positive or ‐negative cell lines and primary ATL cells using DNA microarray and multiple pathway analysis revealed the significant downregulation of the NF‐κB pathway in Tax‐positive cells and cell‐cycle arrest in Tax‐negative cells and primary ATL cells. TAS‐116 suppressed the activator protein‐1 and tumor necrosis factor pathways in all examined cells. These findings strongly indicate the efficacy of TAS‐116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti‐ATL therapeutic agent.