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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

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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 5

MYC hyperactivation is synthetic lethal with XBP1 inhibition.

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MYC hyperactivation is synthetic lethal with XBP1 inhibition.
(A) Clonog...
(A) Clonogenic growth of MCF10AMYC-ER cells transduced with shRNAs against XBP1 or LacZ and treated with different doses of 4-OHT. Ethanol was used as vehicle for 4-OHT. Changes in colony number were compared with vehicle-treated cells expressing shLacZ. (B) Immunoblot of MYC-ER in nuclear extracts of MCF10AMYC-ER cells treated with 4-OHT for 24 hours. (C) Chemical structure of 8866. (D) XBP1-splicing assay in 293T cells that were treated with different doses of 8866 in the presence of DMSO or 5 μg/ml TM for 6 hours. (E) SUM159 cells were treated with DMSO or 5 μM 8866 in the presence of 5 μg/ml TM for 6 hours. ChIP assays were performed using anti-XBP1s antibody. Data are presented relative to input and shown as mean ± SD of technical triplicates. (F) Schematic diagram of fluorescence-based RNA cleavage assay. (G) Cytosolic portions of IRE1 protein or RNase A were incubated with hairpin XBP1 RNA substrate in the presence of various doses of 8866. Cleavage reactions were monitored by fluorescence intensity. (H) Immunoblot of IRE1 phosphorylation (phos-tag SDS-PAGE), ATF6 cleavage (ATF6p), PERK, and eIF2α phosphorylation in 293T cells treated with different doses of 8866 for 6 hours in the presence of DMSO or 5 μg/ml TM. Images shown are representative of 3 independent experiments. (I) Clonogenic growth of MCF10AMYC-ER cells transduced with GFP or XBP1s and treated with DMSO or 5 μM 8866 in the presence of different doses of 4-OHT. Changes in colony number were compared with vehicle-treated (ethanol and DMSO) MCF10AMYC-ER–GFP cells. In A and I, data are presented as mean ± SD of biological triplicates. *P < 0.05; **P < 0.01, 2-tailed unpaired Student’s t test (A) or 1-way ANOVA with Tukey’s multiple comparison test (I).
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