Advanced Science (Jul 2022)
Inhibiting the IRE1α Axis of the Unfolded Protein Response Enhances the Antitumor Effect of AZD1775 in TP53 Mutant Ovarian Cancer
- Rourou Xiao,
- Lixin You,
- Li Zhang,
- Xichen Guo,
- Ensong Guo,
- Faming Zhao,
- Bin Yang,
- Xi Li,
- Yu Fu,
- Funian Lu,
- Zizhuo Wang,
- Chen Liu,
- Wenju Peng,
- Wenting Li,
- Xiaohang Yang,
- Yingyu Dou,
- Jingbo Liu,
- Wei Wang,
- Tianyu Qin,
- Yaoyuan Cui,
- Xiaoxiao Zhang,
- Fuxia Li,
- Yang Jin,
- Qingping Zeng,
- Beibei Wang,
- Gordon B. Mills,
- Gang Chen,
- Xia Sheng,
- Chaoyang Sun
Affiliations
- Rourou Xiao
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Lixin You
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Li Zhang
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xichen Guo
- Key Laboratory of Environment and Health Ministry of Education & Ministry of Environmental Protection and State Key Laboratory of Environmental Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Ensong Guo
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Faming Zhao
- Key Laboratory of Environment and Health Ministry of Education & Ministry of Environmental Protection and State Key Laboratory of Environmental Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Bin Yang
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xi Li
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Yu Fu
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Funian Lu
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Zizhuo Wang
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Chen Liu
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Wenju Peng
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Wenting Li
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xiaohang Yang
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Yingyu Dou
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Jingbo Liu
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Wei Wang
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Tianyu Qin
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Yaoyuan Cui
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xiaoxiao Zhang
- Department of Obstetrics and Gynecology The First Affiliated Hospital of Zhengzhou University Zheng Zhou 450052 China
- Fuxia Li
- Department of gynecology First Affiliated Hospital Shihezi University School of Medicine Shihezi Xinjiang 832000 P. R. China
- Yang Jin
- Department of Biosciences University of Oslo Oslo 0371 Norway
- Qingping Zeng
- Fosun Orinove Inc. Unit 211, Building A4, 218 Xinhu Street Suzhou 215000 China
- Beibei Wang
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Gordon B. Mills
- Department of Cell Development and Cancer Biology Knight Cancer Institute Oregon Health and Sciences University Portland OR 97201 USA
- Gang Chen
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Xia Sheng
- Key Laboratory of Environment and Health Ministry of Education & Ministry of Environmental Protection and State Key Laboratory of Environmental Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- Chaoyang Sun
- National Clinical Research Center for Gynecology and Obstetrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China
- DOI
- https://doi.org/10.1002/advs.202105469
- Journal volume & issue
-
Vol. 9,
no. 21
pp. n/a – n/a
Abstract
Abstract Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA‐like ER kinase (PERK) and inositol‐required enzyme 1α (IRE1α) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF‐κB mediated senescence‐associated secretory phenotype. Upon AZD1775 treatment, activated PERK promotes apoptotic signaling via C/EBP‐homologous protein (CHOP), while IRE1α‐induced splicing of XBP1 (XBP1s) maintains cell survival by repressing apoptosis. This leads to an encouraging synergistic antitumor effect of combining AZD1775 and an IRE1α inhibitor MKC8866 in multiple cell lines and preclinical models of ovarian cancers. Taken together, the data reveal an important dual role of the UPR signaling network in mtTP53 ovarian cancer models in response to AZD1775 and suggest that inhibition of the IRE1α‐XBP1s pathway may enhance the efficacy of AZD1775 in the clinics.
Keywords
