Inhibiting the IRE1α Axis of the Unfolded Protein Response Enhances the Antitumor Effect of AZD1775 in TP53 Mutant Ovarian Cancer

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.

Systematic analysis of cancer‐specific synthetic lethal interactions provides insight into personalized anticancer therapy

“…Of these, TP53 and TTN were detected with higher rates than other genes. Indeed, TP53 mutations were associated with multiple cancers as a potential therapeutic target [33–35], and synthetic lethality between TP53 and ENDOD1 implicated ENDOD1 as a potential cancer‐specific target for drug discovery [36]. Many of these 45 genes were involved in multiple interactions with other genes (median value = 72) (Fig.…”

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

“…The anti-ovarian cancer effects of pimaric acid are mediated by increased p-PERK, PERK, AT-4, CHOP, and IRE-1 levels and cytotoxicity, based on ERS ( 114 ). The WEE1 inhibitor AZD1775 promotes ERS, upregulates GRP78, and activates PERK via CHOP to promote apoptotic signaling, while IRE1α-induces sXBP1 and maintains cell survival by inhibiting apoptosis ( 115 ). The autophagy inhibitor elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation, providing a rational therapeutic strategy in refractory ovarian cancer ( 116 ).…”

Mutational profiling of mitochondrial DNA reveals an epithelial ovarian cancer‐specific evolutionary pattern contributing to high oxidative metabolism

“…[5][6][7][8] Mechanistically, the metabolic reprogramming of mitochondria in cancer cells is implicated in multiple oncogenic alterations, including the activation of nuclear oncogenes (e.g., MYC) and the loss of tumour suppressor gene function (e.g., TP53 and PTEN). 9,10 Nevertheless, these studies primarily focused on the impact of the nuclear genome, neglecting the role of the mitochondrial genome (mitochondrial DNA; mtDNA). The mtDNA is the only genetic material outside the nucleus and contains two major regions, the control region (mtDNA control region; mtCTR) and the coding region (mtDNA coding region; mtCDR).…”

“…For instance, numerous studies have observed a substantial upregulation of genes linked to both OXPHOS and aerobic glycolysis in OC cells 5–8 . Mechanistically, the metabolic reprogramming of mitochondria in cancer cells is implicated in multiple oncogenic alterations, including the activation of nuclear oncogenes (e.g., MYC) and the loss of tumour suppressor gene function (e.g., TP53 and PTEN) 9,10 . Nevertheless, these studies primarily focused on the impact of the nuclear genome, neglecting the role of the mitochondrial genome (mitochondrial DNA; mtDNA).…”