Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells

Abstract

Background Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Methods Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. Results In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Conclusions Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…2 ), PARP1, DNA sensor (or DNA binding protein) IFI16, and Tp53 can also activate the STING pathway signal [ 76 , 208 , 216 ]. Moreover, MUS81 may help activate STING [ 44 , 213 ].…”

“…(4) Increased research is advised regarding combination therapy, including the combination of two DDR inhibitors and immunotherapy. Moreover, the synergistic association of DDR inhibitors with certain defects may achieve more effective and accurate immunomodulation [ 213 ]. For example, ATM inhibitors are used in ATM defective tumors with positive effect [ 252 ].…”

Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy

“…Accordingly, Wee1 inhibition reconstitutes CDK1 activity to reverse resistance of these cancer cells to immune attack ( 194 ). In various cancer models, Wee1 inhibition promotes accumulation of cytosolic dsDNA, leading to activation of the cGAS-STING pathway ( Figure 1 ), increased type I interferon target gene expression when delivered alone ( 195 ), as well as in combination with ATR inhibitors ( 196 ) or immune checkpoint blockade ( 197 ). A STING-independent pathway by which Wee1 inhibition induces the interferon response has also been reported.…”

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

“…156 Although several HER-2 targeted drugs have entered clinical trials for patients with GC, the FDA has approved only trastuzumab for first-line treatment of patients with advanced GC. [239][240][241] In addition, HER-2-targeted CAR-T cell therapy for GC is increasingly gaining attention to avoid drug resistance and improve treatment outcomes. 241,242 Song et al produced genetically modified human T cells that express HER-2-specific CAR consisting of CD137 and CD3ζ, 156 which not only recognized and killed HER-2 + GC cells in vitro but also showed effective and persistent antitumor activity against HER-2 + GC xenografts in vivo.…”