Advances in IKBKE as a potential target for cancer therapy

Yin, Min; Wang, Xin; Lü, Jie

doi:10.1002/cam4.2678

Cited by 42 publications

(32 citation statements)

References 90 publications

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“…IKBKE, a member of the nonclassical IKK family, is considered to be a potential target for cancer therapy. 38 Typically, IKBKE was classified as an oncogenic effector during KRAS-induced pancreatic transformation and activated AKT signaling to promote tumorigenesis. 39 IKBKE-associated cytokine signaling was also shown to promote tumorigenicity of immune-driven triple-negative breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Integrative Characterization of Immune-relevant Genes in Hepatocellular Carcinoma

Hong¹,

Gu²,

Wang³

et al. 2021

Journal of Clinical and Translational Hepatology

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Background and Aims: Tumor microenvironment plays an essential role in cancer development and progression. Cancer immunotherapy has become a promising approach for the treatment of hepatocellular carcinoma (HCC). We aimed to analyze the HCC immune microenvironment characteristics to identify immune-related genetic changes. Methods: Key immune-relevant genes (KIRGs) were obtained through integrating the differentially expressed genes of The Cancer Genome Atlas, immune genes from the Immunology Database and Analysis Portal, and immune differentially expressed genes determined by single-sample gene set enrichment analysis scores. Cox regression analysis was performed to mine therapeutic target genes. A regulatory network based on KIRGs, transcription factors, and immune-related long non-coding RNAs (IRLncRNAs) was also generated. The outcomes of risk score model were validated in a testing cohort and in clinical samples using tissue immunohistochemistry staining. Correlation analysis between risk score and immune checkpoint genes and immune cell infiltration were investigated. Results: In total, we identified 21 KIRGs, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), and found IKBKE, IL2RG, EDNRA, and IGHA1 may be equally important to PD-1 or CTLA4. Meanwhile, KIRGs, various transcription factors, and IRLncRNAs were integrated to reveal that the NRF1-AC127024.5-IKBKE axis might be involved in tumor immunity regulation. Furthermore, the immune-related risk score model was established according to KIRGs and key IRLncRNAs, and verified more obvious discriminating power in the testing cohort. Correlation analysis indicated TNFSF4 , LGALS9 , KIAA1429 , IDO2, and CD276 were closely related to the risk score, and CD4 T cells, macrophages, and neutrophils were the primary immune infiltration cell types. Conclusions: Our results highlight the importance of immune genes in the HCC microenvironment and further unravel the underlying molecular mechanisms in the development of HCC.

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Section: Discussionmentioning

confidence: 99%

Integrative Characterization of Immune-relevant Genes in Hepatocellular Carcinoma

Hong¹,

Gu²,

Wang³

et al. 2021

Journal of Clinical and Translational Hepatology

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“…The IKK-related kinases IKKε and TBK1 are involved in the initiation and progression of several solid tumors. Their inhibition by knock-down or pharmacological drugs has been associated with reduced cancer progression in most cases [29,30]. The impact of TBK1 and IKKε in human malignant melanoma is only scarcely explored.…”

Section: Discussionmentioning

confidence: 99%

The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways

Möller

Wasel

Schmetzer

et al. 2020

IJMS

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Inhibitor-kappaB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IκB kinases, both described as contributors to tumor growth and metastasis in different cancer types. Several hints indicate that they are also involved in the pathogenesis of melanoma; however, the impact of their inhibition as a potential therapeutic measure in this “difficult-to-treat” cancer type has not been investigated so far. We assessed IKKε and TBK1 expression in human malignant melanoma cells, primary tumors and the metastasis of melanoma patients. Both kinases were expressed in the primary tumor and in metastasis and showed a significant overexpression in tumor cells in comparison to melanocytes. The pharmacological inhibition of IKKε/TBK1 by the approved drug amlexanox reduced cell proliferation, migration and invasion. Amlexanox did not affect the cell cycle progression nor apoptosis induction but significantly suppressed autophagy in melanoma cells. The analysis of potential functional downstream targets revealed that NF-кB and ERK pathways might be involved in kinase-mediated effects. In an in vivo xenograft model in nude mice, amlexanox treatment significantly reduced tumor growth. In conclusion, amlexanox was able to suppress tumor progression potentially by the inhibition of autophagy as well as NF-кB and MAP kinase pathways and might therefore constitute a promising candidate for melanoma therapy.

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“…Apart from its tumorigenic function, exerted through various signaling pathways, it also regulates the secretion of inflammatory cytokines and thus affects the tumor microenvironment. 6 Finally in the current study, a risk score model, based on the KIRGs-lncRNA network, was created and evaluated in the testing cohort of patients. It showed good correlation with immune check point genes and infiltration of the microenvironment with CD4, macrophages and neutrophils.…”

mentioning

confidence: 99%

“…Apart from its tumorigenic function, exerted through various signaling pathways, it also regulates the secretion of inflammatory cytokines and thus affects the tumor microenvironment. 6 …”

mentioning

confidence: 99%