EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers

Möck, Andreas; Plath, Michaela; Moratin, Julius; Tapken, Maria Johanna; Jäger, Dirk; Krauß, Jürgen; Fröhling, Stefan; Heß, Jochen; Zaoui, Karim

doi:10.3389/fonc.2021.678966

Cited by 19 publications

(15 citation statements)

References 48 publications

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“…However, tumors might exhibit accelerated MEK-ERK pathway activity despite missing MAPK pathway mutations due to the activation of upstream regulators (e.g., EGFR) by genomic alterations or high levels of stimulating ligands [78]. This assumption is in line with computational inferred pathway activities, which are not necessarily associated with the mutational landscape of key components in the respective pathways as demonstrated recently for EGFR or PI3K pathways [78,79].…”

Section: Discussionsupporting

confidence: 59%

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Feng

Wang

Herpel

et al. 2021

Cancers

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Squamous cell carcinoma (SCC) is the most prevalent histological type of human cancer, including head and neck squamous cell carcinoma (HNSCC). However, reliable prognostic gene signatures for SCC and underlying genetic and/or epigenetic principles are still unclear. We identified 37 prognostic candidate genes by best cutoff computation based on survival in a pan-SCC cohort (n = 1334) of The Cancer Genome Atlas (TCGA), whose expression stratified not only the pan-SCC cohort but also independent HNSCC validation cohorts into three distinct prognostic subgroups. The most relevant prognostic genes were prioritized by a Least Absolute Shrinkage and Selection Operator Cox regression model and were used to identify subgroups with high or low risks for unfavorable survival. An integrative analysis of multi-omics data identified FN1, SEMA3A, CDH2, FBN1, COL5A1, and ADAM12 as key nodes in a regulatory network related to the prognostic phenotype. An in-silico drug screen predicted two MEK inhibitors (Trametinib and Selumetinib) as effective compounds for high-risk SCC based on the Cancer Cell Line Encyclopedia, which is supported by a higher p-MEK1/2 immunohistochemical staining of high-risk HNSCC. In conclusion, our data identified a molecular classifier for high-risk HNSCC as well as other SCC patients, who might benefit from treatment with MEK inhibitors.

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Section: Discussionsupporting

confidence: 59%

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Feng

Wang

Herpel

et al. 2021

Cancers

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“…After annotation by the GTF files, 545 DNA repair genes were eventually used for subsequent analyses. GSE41613 (15), GSE27020 (16), GSE117973 (17), and GSE65858 (18) datasets with transcriptome and clinical data of patients with HNSCC were downloaded from Gene Expression Omnibus (https://www. ncbi.nlm.nih.gov/geo/) for external validation.…”

Section: Data Downloadmentioning

confidence: 99%

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma

et al. 2021

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PurposeTo construct a prognostic signature composed of DNA repair genes to effectively predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC).MethodsAfter downloading the transcriptome and clinical data of HNSCC from the Cancer Genome Atlas (TCGA), 499 patients with HNSCC were equally divided into training and testing sets. In the training set, 13 DNA repair genes were screened using univariate proportional hazard (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a risk model, which was validated in the testing set.ResultsIn the training and testing sets, there were significant differences in the clinical outcomes of patients in the high- and low-risk groups showed by Kaplan-Meier survival curves (P < 0.001). Univariate and multivariate Cox regression analyses showed that the risk score had independent prognostic predictive ability (P < 0.001). At the same time, the immune cell infiltration, immune score, immune-related gene expression, and tumor mutation burden (TMB) of patients with HNSCC were also different between the high- and low-risk groups (P < 0.05). Finally, we screened several chemotherapeutics for HNSCC, which showed significant differences in drug sensitivity between the high- and low-risk groups (P < 0.05).ConclusionThis study constructed a 13-DNA-repair-gene signature for the prognosis of HNSCC, which could accurately and independently predict the clinical outcome of the patient. We then revealed the immune landscape, TMB, and sensitivity to chemotherapy drugs in different risk groups, which might be used to guide clinical treatment decisions.

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“…This current study showed that the EGFR, PI3K, and NF-κB signaling is downregulated and upregulated in PCa by USP8 silencing and overexpressing, respectively ( Figure 4 ). Moreover, PI3K/Akt is a well-established downstream target of EGFR, which is generally activated by EGFR autophosphorylation leading to cell proliferation and growth ( 33 – 35 ). However, the underlining mechanism of USP8 in regulating EGFR and PI3K targeting to activate the NF-κB signaling pathway in PCa is not clearly stated yet.…”

Section: Resultsmentioning

confidence: 99%

Knockdown of USP8 inhibits prostate cancer cell growth, proliferation, and metastasis and promotes docetaxel’s activity by suppressing the NF-kB signaling pathway

Islam

Chen

et al. 2022

Front. Oncol.

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Ubiquitin-specific protease 8 (USP8) has been recently reported to be involved in tumorigenesis. Prostate cancer (PCa) is the most diagnosed malignancy among men, but USP8’s role in PCa is not yet investigated comprehensively. Therefore, the PCa cell lines DU145 and PC3 were transfected with USP8 siRNA or overexpressing vector together with or without docetaxel. The silencing USP8 and docetaxel treatment reduced cell viability and migration and promoted apoptosis. In contrast, USP8 knockdown was found to enhance docetaxel antitumor activity. In contrast, increased cell viability and migration were noticed upon USP8 overexpression, thereby decreasing apoptosis and suppressing docetaxel antitumor activity. Notably, although EGFR, PI3K, and NF-kB were found to be increased in both USP8 overexpression and docetaxel treatment, it significantly attenuated the effects in USP8 silencing followed by with or without docetaxel. Although EGFR silencing decreased PI3K and NF-kB activation, overexpression of USP8 was shown to counteract SiEGFR’s effects on NF-kB signaling by increasing PI3K expression. Our findings revealed that USP8 plays an oncogenic role in PCa and can suppress docetaxel activity. Additionally, as EGFR/PI3K/NF-kB was previously reported to develop docetaxel resistance, the combination treatment of USP8 knockdown with docetaxel might be a potential PCa therapeutic.

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EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers

Cited by 19 publications

References 48 publications

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma

Knockdown of USP8 inhibits prostate cancer cell growth, proliferation, and metastasis and promotes docetaxel’s activity by suppressing the NF-kB signaling pathway

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