IκB Kinase α Is Required for Development and Progression of <i>KRAS</i>-Mutant Lung Adenocarcinoma

Vreka, Malamati; Lilis, Ioannis; Papageorgopoulou, Maria; Giotopoulou, Georgia A.; Lianou, Marina; Giopanou, Ioanna; Kanellakis, Nikolaos I.; Spella, Magda; Agalioti, Theodora; Armenis, Vasileios; Goldmann, Torsten; Marwitz, Sebastian; Yull, Fiona E.; Blackwell, Timothy S.; Pasparakis, Manolis; Marazioti, Antonia; Stathopoulos, Georgios T.

doi:10.1158/0008-5472.can-17-1944

Cited by 39 publications

(62 citation statements)

References 49 publications

(93 reference statements)

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“…The mammalian NF-kB family has subunits including RelA (P65), RelB, NF-kB1 (P50/P105), NF-kB2 (P52/P100) and c-Rel. The pathways of NF-kB activation consist of canonical (or classical) pathway mediated by RelA/P50 or c-Rel/P50 dimers and non-canonical (or alternative) pathway mediated by RelB/P52 dimer [ 31 , 32 ]. Studies have suggested that canonical pathway generally performs as tumor promoting and anti-apoptotic roles, while non-canonical pathway has tumor suppressing and facilitating apoptosis effects within cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of NF-κB expression in non-small cell lung cancer: A meta-analysis

Wang

Zuo

et al. 2018

PLoS ONE

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Nuclear factor kappa B (NF-κB), a key nuclear transcription factor, is associated with prognosis in a variety of human cancers. However, the clinical value of NF-κB in non-small cell lung cancer (NSCLC) is still controversial. Therefore, the aim of this meta-analysis was to obtain an accurate evaluation of the relationship between NF-κB expression and survival prognosis of NSCLC patients based on published articles. PubMed, EMBASE and Web of Science databases were systematically searched for potential articles. A total of 1159 patients from 7 eligible studies comparing prognostic significance of NF-κB expression levels in NSCLC were included in our meta-analysis. I2 statistic and P value were performed to evaluate heterogeneity. The results of analysis were presented as hazard ratio (HR) or odds ratios (OR) with 95% confidence interval (95% CI). Subgroup analysis based on ethnicity of NSCLC patients and NF-kB cellular localization within cancer cells were conducted to illustrate the potential discrepancy. Significant heterogeneity was considered at I2>50% and P<0.05, and random-effects model was used. The combined results indicated that higher NF-κB expression was associated with shorter overall survival (OS) of NSCLC patients (HR = 2.78, 95% CI = 1.51–5.12, P = 0.001). Moreover, NF-κB expression was closely associated with tumor stage (HR = 0.32, 95% CI = 0.18–0.57, P<0.0001), lymph node metastasis (HR = 0.56, 95% CI = 0.38–0.83, P = 0.004) and 5-year OS for NSCLC patients (OR = 1.83, 95% CI = 1.02–3.31, P = 0.04). We conclude that NF-κB expression may be a potential unfavorable prognostic marker for NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of NF-κB expression in non-small cell lung cancer: A meta-analysis

Wang

Zuo

et al. 2018

PLoS ONE

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“…Autochthonous cancer models. Chemical-induced lung adenocarcinoma was induced in FVB mice by a single intraperitoneal exposure to 1 g/kg urethane 68 . KRASG12D-driven LADC was induced via intratracheal injections of 5 × 10 8 plaque-forming units (PFU) adenovirus type 5 encoding CRE recombinase (Ad-Cre) to LSL.KRASG12D mice on the C57BL/6 background 69 .…”

Section: Reagents and Resources Reagents And Resources Are Included Inmentioning

confidence: 99%

Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

et al. 2019

Self Cite

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Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

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“…These studies collectively identify IKKβ inhibition as a promising therapeutic strategy in KRAS-driven lung cancer with altered p53 activity [ 65 ]. It should be noted, however, that several studies have also linked KRAS-driven IKKα and TBK1 activation to pathogenic NF-κB activity [ 181 , 182 , 183 , 184 ], suggesting that IKKβ inhibition alone may not be an optimal therapeutic strategy.…”

Section: Recent Therapeutic Opportunities To Target Ikkβmentioning

confidence: 99%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

108

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Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.

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IκB Kinase α Is Required for Development and Progression of KRAS-Mutant Lung Adenocarcinoma

Cited by 39 publications

References 49 publications

Prognostic significance of NF-κB expression in non-small cell lung cancer: A meta-analysis

Prognostic significance of NF-κB expression in non-small cell lung cancer: A meta-analysis

Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

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