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

• Published in: The Journal of clinical investigation Vol. 128; no. 4; pp. 1283 - 1299
• Main Authors: Zhao, Na, Cao, Jin, Xu, Longyong, Tang, Qianzi, Dobrolecki, Lacey E., Lv, Xiangdong, Talukdar, Manisha, Lu, Yang, Wang, Xiaoran, Hu, Dorothy Z., Shi, Qing, Xiang, Yu, Wang, Yunfei, Liu, Xia, Bu, Wen, Jiang, Yi, Li, Mingzhou, Gong, Yingyun, Sun, Zheng, Ying, Haoqiang, Yuan, Bo, Lin, Xia, Feng, Xin-Hua, Hartig, Sean M., Li, Feng, Shen, Haifa, Chen, Yiwen, Han, Leng, Zeng, Qingping, Patterson, John B., Kaipparettu, Benny Abraham, Putluri, Nagireddy, Sicheri, Frank, Rosen, Jeffrey M., Lewis, Michael T., Chen, Xi
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2018
• Subjects: Activating transcription factor 1; Animal models; Animals; Biomedical research; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cancer treatment; Care and treatment; Cell Line, Tumor; Chemotherapy; Development and progression; Docetaxel - pharmacology; Drug Delivery Systems; Endoplasmic reticulum; Endoribonucleases - genetics; Endoribonucleases - metabolism; Enzymes; Female; Genes; Genetic aspects; Genetic engineering; Health aspects; Humans; Inositol; Kinases; Mice; Molecular modelling; Myc protein; Nucleotidases; Pharmacological research; Phosphorylation; Physiological aspects; Protein folding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Response Elements; Ribonuclease; Saccharomyces cerevisiae; Signal Transduction - drug effects; Signal Transduction - genetics; Stem cells; Transcription; Transcription factors; Tumors; Unfolded Protein Response - drug effects; Unfolded Protein Response - genetics; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism; Xenograft Model Antitumor Assays; Xenografts; United States > US; Oncology; Breast cancer; Cell stress; Drug therapy; Therapeutics
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI95873

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.