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.
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Research Article Oncology Therapeutics

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

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Figure 4

MYC interacts with XBP1s and regulates XBP1s transcriptional activity.

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MYC interacts with XBP1s and regulates XBP1s transcriptional activity. (...
(A–C) ChIP assays of SUM159 cells (A) and MC1 PDX tumors (B and C) were performed using anti-MYC or anti-XBP1s antibodies to detect enriched gene-promoter fragments. IgG was used as mock control. Genomic region upstream of VEGFA lacking XBP1s- and MYC-binding sites was used as a negative control (Ctrl). Data are presented relative to input and shown as mean ± SD of technical triplicates. (D) ChIP-re-ChIP assay of SUM159 cells was performed using the anti-MYC antibody first (MYC ChIP). Eluents were subjected to a second ChIP assay using IgG (IgG reChIP) or anti-XBP1s antibody (XBP1s reChIP) to detect enriched gene-promoter fragments. ND, not detected by qPCR assay. Data are shown as mean ± SD of technical triplicates. (E and F) Flag-tagged MYC and HA-tagged XBP1s were coexpressed in 293T cells and coimmunoprecipitation was performed with anti-HA antibody (E) or anti-Flag antibody (F). The immunoblot was probed with anti-Flag and anti-HA antibodies. HA-GFP (E) or Flag-GFP (F) was used as control. (G and H) Nuclear extracts from TM-treated SUM159 cells were subjected to coimmunoprecipitation with anti-XBP1s antibody (G) or anti-MYC antibody (H). The immunoblot was probed with anti-XBP1s and anti-MYC antibodies. (I–L) UPRE or ERSE reporter was cotransfected with MYC or XBP1s or both expression plasmids into BT549 (I and K) or 293T (J and L) cells. Luciferase activity was measured 48 hours after transfection. In I–L, GFP expression plasmid was used as control. Data are presented relative to Renilla readings and shown as mean ± SD of biological triplicates. All results shown are representative of 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired Student’s t test (D) or 1-way ANOVA with Tukey’s multiple comparison test (I–L).