ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

// Xun Yuan 1, 2 , Dhonghyo Kho 2 , Jing Xu 2 , Ambikai Gajan 2 , Kongming Wu 1 , Gen Sheng Wu 2 1 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China 2 Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA Correspondence to: Gen Sheng Wu, email: wug@karmanos.org Kongming Wu, email: kmwu@tjh.tjmu.edu.cn Keywords: ONC201, triple-negative breast cancer, TRAIL, ATF4, apoptosis Received: December 20, 2016     Accepted: January 24, 2017     Published: February 17, 2017 ABSTRACT ONC201 was previously identified as a first-in-class antitumor agent and small-molecule inducer of the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) gene that induces apoptosis in cancer cells. ONC201 has a safety profile and is currently in phase II clinical trials for the treatment of various malignancies. In the current study, we examine the effect of ONC201 on triple-negative breast cancer cells (TNBC), a subtype of breast cancer that is sensitive to TRAIL. We find that ONC201 inhibits the growth of TNBC cells including TNBC cells that have developed acquired TRAIL resistance. However, TNBC cells that have developed acquired ONC201 resistance are cross-resistant to TRAIL. Mechanistically, ONC201 triggers an integrated stress response (ISR) involving the activation of the transcription factor ATF4. Knockdown of ATF4 impairs ONC201-induced apoptosis of TNBC cells. Importantly, the activation of ATF4 is compromised in ONC201-resistant TNBC cells. Thus, our results indicate that ONC201 induces an ISR to cause TNBC cell death and suggest that TNBC patients may benefit from ONC201-based therapies.