Abstract 2702: Therapeutic potentials of STAT5 inhibitors in overcoming bortezomib resistance in human T-cell leukemia

Abstract The purpose of our study is to define the mechanism of bortezomib resistance in cancer therapy and to identify novel approaches in overcoming the resistance. Bortezomib is the first FDA-approved reversible proteasome inhibitor in treating multiple myeloma and mantle cell lymphoma patients. Numerous clinical trials are ongoing in testing the efficacy of bortezomib and its derivatives in treating human cancers. One of the major concerns in using single-agent bortezomib is that patients develop resistance during the course of treatment and cancers relapse. To explore the underlying mechanisms, we recently established a bortezomib-resistant human acute T lymphoblastic cell line Jurkat-BR. Jurkat-BR remains sensitive to carfilzomib, a FDA-approved second-generation irreversible proteasome inhibitor. An inhibitor targeting upstream proteasome pathway, MLN 4924, also exhibits cytotoxic effects toward Jurkat-BR. Overexpression and hyperactivation of signal transducer and activator of transcription 5 (STAT5) is associated with many forms of blood malignancies. Compared with parental Jurkat, Jurkat-BR has significant elevation of STAT5b, but not STAT5a, at both mRNA and protein levels. Pimozide is an antipsychotic drug that recently found to specifically inhibit STAT5 activity. Consistent with STAT5b overexpression, Jurkat-BR is more sensitive than parental Jurkat to cytotoxicity induced by pimozide. Another inhibitor targeting STAT5 SH2 domain, the nonpeptidic nicotinoyl hydrazone (CAS# 285968-31-4, STAT5I) also exhibits similar effects. Both pimozide and STAT5I synergize with bortezomib in killing Jurkat-BR cells. These results support the importance of STAT5b upregulation in acquired bortezomib resistance. We reported previously that STAT5 translocates to mitochondria (BBRC 402:778) and represses mitochondrial gene expression (manuscript submitted). In Jurkat-BR cells, we also observed STAT5b mitochondrial translocation, reduced mitochondrial gene expression, and repression of mitochondrial respiration. These results suggest that both STAT5b overexpression and reduced mitochondrial activity may be important molecular markers for cancer cell's resistance to bortezomib. Our data further support the clinical benefit of STAT5 inhibitors in complementing proteasome inhibitors and in overcoming its resistance in patients who acquire resistance through upregulating STAT5. More importantly, the link between reduced mitochondrial respiration and bortezomib resistance highlights the potentials of targeting mitochondria in developing novel combined chemotherapy for cancer patients. Citation Format: Fu-Yu Chueh, Shahrooz Vahedi, Fu-Shin Chueh, Chao-Lan Yu. Therapeutic potentials of STAT5 inhibitors in overcoming bortezomib resistance in human T-cell leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2702. doi:10.1158/1538-7445.AM2015-2702