Checkpoint Kinase 1 (Chk1) inhibition fails to activate the Stimulator of Interferon Genes (STING) innate immune signalling in a human coculture cancer system

Brooks, Teresa; Wayne, Joanne; Massey, Andrew

doi:10.1186/s43556-021-00044-1

Cited by 6 publications

(4 citation statements)

References 49 publications

(65 reference statements)

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“…However, dysregulation of cGAS-STING observed here in both human and mouse melanomas appears to be a common feature of melanomas that contributes to the immune evasion of these tumours [44]. Furthermore, it has recently been reported that CHK1i does not activate cGAS-STING signalling even in cells where this pathway is functional, and actually inhibits cGAS-STING pathway activation of IRF3 [45]. The ability of CHK1i+LDHU to promote strong pro-inflammatory cytokine/chemokine expression independent of this pathway suggests other pathways such as NF-κB observed in mouse melanoma.…”

Section: Discussionmentioning

confidence: 59%

Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression

Proctor

Cruz

Daignault-Mill

et al. 2021

Cancers

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Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8+ T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4+ Treg and FoxP3+ NKT cells. The number of these accumulated during treatment, the increase in FoxP3+ NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effector to suppressive NKT cells. Whereas tumour infiltrating CD8+ T cell PD-1 and tumour PD-L1 expression was increased with treatment, peripheral CD4+ and CD8+ T cells retained strong anti-tumour activity. Despite increased CD8+ T cell PD-1, combination with anti-PD-1 did not improve response, indicating that immunosuppression from Tregs and FoxP3+ NKT cells are major contributors to the immunosuppressive tumour microenvironment. This demonstrates that therapies targeting replication stress can be well tolerated, not adversely affect immune responses, and trigger an effective anti-tumour immune response.

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Section: Discussionmentioning

confidence: 59%

Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression

Proctor

Cruz

Daignault-Mill

et al. 2021

Cancers

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“…The checkpoint kinase 1 (CHK1) inhibitor prexasertib induces DNA damage in cancer cells and activates the STING/TBK1/IRF3 innate immune pathway 106 , thereby increasing levels of chemokines such as CXCL10 and CCL5, and inducing activation of cytotoxic T lymphocytes 107 . Another study has reported that CHK1 inhibition increases TBK1 phosphorylation but not IRF3 phosphorylation, and does not induce IRF or NF-κB reporter gene activation 108 . In a phase II trial on recurrent ovarian cancer, treatment with prexasertib has been found to upregulate activation markers of the STING pathway such as TBK1, which correlates with prolonged progression-free survival (9 months vs. 3 months, P = 0.003) 109 .…”

Section: Strategies For Harnessing the Cgas-sting Pathway In Cancer T...mentioning

confidence: 99%

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

Zhang,

Yu,

Peng

et al. 2024

Cancer Biol Med

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The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment. Within this landscape, the innate immune system, a critical sentinel protecting against tumor incursion, is a key player. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway has been found to be a linchpin of innate immunity: activation of this signaling pathway orchestrates the production of type I interferon (IFN-α/β), thus fostering the maturation, differentiation, and mobilization of immune effectors in the tumor microenvironment. Furthermore, STING activation facilitates the release and presentation of tumor antigens, and therefore is an attractive target for cancer immunotherapy. Current strategies to activate the STING pathway, including use of pharmacological agonists, have made substantial advancements, particularly when combined with immune checkpoint inhibitors. These approaches have shown promise in preclinical and clinical settings, by enhancing patient survival rates. This review describes the evolving understanding of the cGAS-STING pathway’s involvement in tumor biology and therapy. Moreover, this review explores classical and non-classical STING agonists, providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies. Despite challenges and complexities, the cGAS-STING pathway, a promising avenue for enhancing cancer treatment efficacy, has the potential to revolutionize patient outcomes.

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“…In conjunction with certain cytotoxic therapies, checkpoint kinase 1 (Chk1) inhibition modifies the internal cellular environment but sometimes suppresses expected responses [247]. One proposed solution is to supplement Chk1 inhibitors with STING agonists [248].…”

Section: Immunotherapies Such As Oncolytic Viruses (Ov)mentioning

confidence: 99%

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

Korneenko,

Pestov,

Nevzorov

et al. 2023

Pharmaceuticals

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The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

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Checkpoint Kinase 1 (Chk1) inhibition fails to activate the Stimulator of Interferon Genes (STING) innate immune signalling in a human coculture cancer system

Cited by 6 publications

References 49 publications

Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression

Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

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