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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

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 2

MYC is sufficient for activation of the IRE1/XBP1 pathway.

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MYC is sufficient for activation of the IRE1/XBP1 pathway.
(A) Schematic...
(A) Schematic representation of the MCF10AMYC-ER system. In the presence of 4-OHT, MYC-ER fusion protein translocates to the nucleus and transactivates the MYC target genes. (B) Immunoblot and XBP1 splicing assay (RT-PCR) of MCF10AMYC-ER cells treated with different doses of 4-OHT for 24 hours. MYC-ER, XBP1s, and TBP were detected from nuclear extracts (NE) and IRE1 from whole cell lysates. TBP, actin, and GAPDH were used as loading control. (C and D) qRT-PCR analysis of the expression of IRE1, XBP1s, XBP1 t, XBP1 s/t (C), and XBP1 target genes (D) in MCF10AMYC-ER cells treated with different doses of 4-OHT for 24 hours. (E and F) The tissue microarray containing specimens from 60 breast cancer patients was subjected to IHC for MYC and IRE1 (DAB staining, brown). (E) Representative photographs are shown indicating weak, moderate, and strong staining. Scale bars: 50 μm. (F) MYC H-score in tissue microarray samples with distinct IRE1 intensities. Data in qRT-PCR analysis are presented relative to actin and shown as mean ± SD of technical triplicates. Tissue microarray was performed once, and all other data are representative of 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Tukey’s multiple comparison test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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