ONC201 selectively induces apoptosis in cutaneous T-cell lymphoma cells via activating pro-apoptotic integrated stress response and inactivating JAK/STAT and NF-κB pathways

// Xiao Ni 1 , Xiang Zhang 1 , Cheng-Hui Hu 1 , Timothy Langridge 1 , Rohinton S. Tarapore 2 , Joshua E. Allen 2 , Wolfgang Oster 2 and Madeleine Duvic 1 1 Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Oncoceutics, Inc., Philadelphia, PA, USA Correspondence to: Xiao Ni, email: xiaoni@mdanderson.org Keywords: NHL, ONC201, TIC10, TRAIL, cancer Received: December 22, 2016     Accepted: May 22, 2017     Published: June 27, 2017 ABSTRACT Cutaneous T-cell lymphomas (CTCLs) are extremely symptomatic and still incurable, and more effective and less toxic therapies are urgently needed. ONC201, an imipridone compound, has shown efficacy in pre-clinical studies in multiple advanced cancers. This study was to evaluate the anti-tumor activity of ONC201 on CTCL cells. The effect of ONC201 on the cell growth and apoptosis were evaluated in CTCL cell lines (n=8) and primary CD4 + malignant T cells isolated from CTCL patients (n=5). ONC201 showed a time-dependent cell growth inhibition in all treated cell lines with a concentration range of 1.25-10.0 μM. ONC201 also induced apoptosis in tested cells with a narrow concentration range of 2.5-10.0 μM, evidenced by increased Annexin V + cells, accompanied by accumulated sub-G1 portions. ONC201 only induced apoptosis in CD4 + malignant T cells, not in normal CD4 + T cells. The activating transcription factor 4 (ATF4), a hallmark of integrated stress response, was upregulated in response to ONC201 whereas Akt was downregulated. In addition, molecules in JAK/STAT and NF-κB pathways, as well as IL-32β, were downregulated following ONC201 treatment. Thus, ONC201 exerts a potent and selective anti-tumor effect on CTCL cells. Its efficacy may involve activating integrated stress response through ATF4 and inactivating JAK/STAT and NF-κB pathways.