ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma

Sheng, Hailong; Huang, Yan; Xiao, Yazhi; Zhu, Zhenru; Shen, Mengying; Zhou, Pengyu; Guo, Ze-Qin; Wang, Jian; Wang, Hui; Dai, Weiyu; Zhang, Wanjun; Sun, Jiaqian; Cao, Chuanhui

doi:10.1136/jitc-2019-000340

Cited by 165 publications

(126 citation statements)

References 39 publications

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“…ATR inhibition potentiated type I IFN production in concert with IR in a cGAS–STING-dependent manner [ 97 ]. Moreover, ATR inhibition in combination with IR and immune checkpoint blockade resulted in superior antitumor efficacy in hepatocellular carcinoma models in a cGAS–STING-mediated manner [ 123 ]. As mentioned previously, one of the drawbacks of radiation-induced activation of the STING pathway is recruitment of immunosuppressive MDSCs to the TME [ 113 ].…”

Section: Augmenting Sting Signaling To Enhance Radiation-induced Amentioning

confidence: 99%

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

136

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Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

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Section: Augmenting Sting Signaling To Enhance Radiation-induced Amentioning

confidence: 99%

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

136

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“…The immune microenvironment plays a positive and negative role in the occurrence, development and invasion of cancer. In general, the stronger the immune cell invasion in the tumor microenvironment, the more able to inhibit tumor progression [39][40][41][42]. There are three processes in the immune response of cancer: elimination, balance and escape.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis of Genes Associated With Cancer Stem Cell Characteristics via Stemness Indices Combined With Multi-Omics Data in Liver Cancer

Zhang¹,

Yu²,

Chu³

et al. 2020

Preprint

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BackgroundLiver cancer (LC) is one of the most prevalent malignancies with a high morbidity and mortality. Cancer stem cells (CSCs) are capable of tumorigenicity, self-renewal and long-term survival. However, the relationship between LC and CSCs remains unclear.MethodsThe clinical data of LC patients and multi-omics data including mRNA-seq, lncRNA-seq, miRNA-seq, mRNA expression-based stemness index (mRNAsi), alternative splicing, DNA methylation and copy number variation (CNV) were obtained from The Cancer Genome Atlas (TCGA). Besides, the clinical data and RNA-seq of validation group were obtained from International Cancer Genome Consortium (ICGC). Integrative analysis of genes associated with CSCs characteristics were performed by stemness indices combined with multi-omics data in LC.ResultsThe stemness degree of cells in liver tumor group was higher than that of the normal group. The patients with high stemness degree of tumor tissue had significantly poorer overall survival. Besides, 6 methylation-driven genes and 4 CNV-driven genes related to CSCs characteristics were obtained. Alternative splicing factor regulatory network and ceRNA regulatory network were constructed respectively. Furthermore, the mRNAsi score of LC was negatively correlated with the tumor immune score. The proportion of CD8 T cell, activated memory CD4 T cell, follicular helper T cell and M1 macrophages was up-regulated in tumors with a higher degree of stemness. Finally, a prediction model was established, which has been proved to be a good predictor of prognosis by ICGC data.ConclusionsCancer cells with high degree of stemness aggravated the malignant progression of LC, which may be related to low immune infiltration. The proposed prediction model was a powerful predictor for patients and helpful to clinical work.

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“…Various studies have shown that other DDR inhibitors, such as ATR, WEE1, and CHK1 inhibitors, have synergistic effects with immune checkpoint inhibitors. Sheng et al [150] demonstrated that AZD6738 enhances the efficacy of immune checkpoint inhibitors and radiotherapy in hepatocellular carcinoma. The synergistic antitumor effect of AZD6738 and radioimmunotherapy combination therapy depended on cyclic GMP-AMP synthase (cGAS)/STING signaling pathway activation.…”

Section: Ddr Inhibitors and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

et al. 2020

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Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.

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ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma

Cited by 165 publications

References 39 publications

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Integrative Analysis of Genes Associated With Cancer Stem Cell Characteristics via Stemness Indices Combined With Multi-Omics Data in Liver Cancer

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

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