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 CuiXiaoxiao Zhang, Fuxia Li, Yang Jin, Qingping Zeng, Beibei Wang, Gordon B. Mills, Gang Chen, Xia Sheng, Chaoyang Sun

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number2105469
JournalAdvanced Science
Volume9
Issue number21
DOIs
StatePublished - Jul 25 2022

Keywords

  • AZD1775
  • UPR
  • WEE1
  • mutant TP53
  • ovarian cancer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering(all)
  • Physics and Astronomy(all)

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