@article{8b51939ce36d4ac2b1aa3f608301b45a,
title = "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.",
author = "Na Zhao and Jin Cao and Longyong Xu and Qianzi Tang and Dobrolecki, {Lacey E.} and Xiangdong Lv and Manisha Talukdar and Yang Lu and Xiaoran Wang and Hu, {Dorothy Z.} and Qing Shi and Yu Xiang and Yunfei Wang and Xia Liu and Wen Bu and Yi Jiang and Mingzhou Li and Yingyun Gong and Zheng Sun and Haoqiang Ying and Bo Yuan and Xia Lin and Feng, {Xin Hua} and Hartig, {Sean M.} and Feng Li and Haifa Shen and Yiwen Chen and Leng Han and Qingping Zeng and Patterson, {John B.} and Kaipparettu, {Benny Abraham} and Nagireddy Putluri and Frank Sicheri and Rosen, {Jeffrey M.} and Lewis, {Michael T.} and Xi Chen",
note = "Funding Information: We thank Qin Yan (Yale University) for providing the iCas9 system. We are grateful to Yi Li, Xiang Zhang, and Thomas West-brook (Baylor College of Medicine) for advice and discussions. This work was supported by the National Cancer Institute (NCI) (5P50CA186784-03 SPORE Career Development Award to XC and SPORE Supplement Award to MTL and LED), the Cancer Prevention and Research Institutes of Texas (CPRIT) (RR150009 to XC; RR140071 to YC), Susan G. Komen for the Cure (CCR16380871 to XC), the NIH (R01CA148761 to JMR; R00CA175290 to YC; R01DK114356 and R03DK105006 to SMH), the Cytometry and Cell Sorting Core (funded by NIH P30 AI036211,P30 CA125123, and S10 RR024574), and PDX and Advance In Vivo Models Core at Baylor College of Medicine (funding from RP170691 CPRIT Core Facility Support Award and NCI-CA125123 P30 Cancer Center Support Grant). Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Investigation. All rights reserved. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",
year = "2018",
month = apr,
day = "2",
doi = "10.1172/JCI95873",
language = "English (US)",
volume = "128",
pages = "1283--1299",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",
}