期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 4, 页码 1283-1299出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI95873
关键词
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资金
- National Cancer Institute (NCI) [5P50CA186784-03]
- Cancer Prevention and Research Institutes of Texas (CPRIT) [RR150009, RR140071]
- Susan G, Komen for the Cure [CCR16380871]
- NIH [R01CA148761, R00CA175290, R01DK114356, R03DK105006]
- Cytometry and Cell Sorting Core (NIH) [P30 A1036211, P30 CA125123, S10 RR024574]
- Advance In Vivo Models Core at Baylor College of Medicine [RP170691, NCI-CA125123 P30]
- NATIONAL CANCER INSTITUTE [P50CA186784, R01CA148761, R00CA175290, R21CA215591, P30CA125123, P30CA016672] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR024574] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI036211] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK114356, R01DK111436, R03DK105006] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES027544] Funding Source: NIH RePORTER
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.
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