Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer
Na Zhao, … , Michael T. Lewis, Xi Chen
Na Zhao, … , Michael T. Lewis, Xi Chen
Published February 26, 2018
Citation Information: J Clin Invest. 2018;128(4):1283-1299. https://doi.org/10.1172/JCI95873.
View: Text | PDF
Research Article Oncology

Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer

Abstract

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Authors

Na Zhao, Jin Cao, Longyong Xu, Qianzi Tang, Lacey E. Dobrolecki, Xiangdong Lv, Manisha Talukdar, Yang Lu, Xiaoran Wang, Dorothy Z. Hu, Qing Shi, Yu Xiang, Yunfei Wang, Xia Liu, Wen Bu, Yi Jiang, Mingzhou Li, Yingyun Gong, Zheng Sun, Haoqiang Ying, Bo Yuan, Xia Lin, Xin-Hua Feng, Sean M. Hartig, Feng Li, Haifa Shen, Yiwen Chen, Leng Han, Qingping Zeng, John B. Patterson, Benny Abraham Kaipparettu, Nagireddy Putluri, Frank Sicheri, Jeffrey M. Rosen, Michael T. Lewis, Xi Chen

×

Figure 6

IRE1 RNase inhibitor 8866 suppresses growth of patient-derived tumors with high MYC expression.

Options: View larger image (or click on image) Download as PowerPoint
IRE1 RNase inhibitor 8866 suppresses growth of patient-derived tumors wi...
(A) Immunostaining of MYC in human normal mammary gland or PDX tumors. Normal mammary gland without primary antibody incubation was used as negative control. Scale bars: 50 μm. (B) Immunoblot of MYC in PDX models. (C) Schematic of treatment strategy with 8866. (D) Tumor volume quantification of established MC1 PDX tumors in SCID/beige mice treated with vehicle or 8866. Data are presented as mean ± SEM. (E) Kaplan-Meier survival curve of MC1 PDX tumor–bearing mice from treatment start time in vehicle (n = 6) and 8866 (n = 7) treatment groups. (F) RT-PCR analysis of XBP1 splicing in vehicle-treated (n = 6) and 8866-treated (n = 7) MC1 PDX tumor samples harvested at the end of the experiment. (G) qRT-PCR analysis of XBP1 target gene expression in vehicle-treated and 8866-treated MC1 PDX tumor samples harvested at the end of the experiment. Data are presented as mean ± SD of biological replicates, and actin was used as internal control. (H) H&E, cleaved caspase-3, or CD31 immunostaining of MC1 PDX tumors harvested at the end of the experiment. Scale bars: 50 μm. (I and J) Quantification of CD31-positive cells (I) or cleaved caspase-3–positive cells (J) on tumor sections from vehicle-treated (n = 6) or 8866-treated (n = 7) MC1 PDX mice. (K–M) Tumor volume quantification (upper panel) and Kaplan-Meier survival curve (lower panel) of 4913 (K), 2147 (L), and 4195 (M) PDX tumor–bearing mice treated with vehicle or 8866. Data are presented as mean ± SEM. The log-rank test was used to test for the significant differences of survival between the groups (E, K–M). *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA with Bonferroni’s post test (D, K–M) or 2-tailed unpaired Student’s t test (G, I, J).