MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma

Jain, Ankit; Patel, Krishna; Pinto, Sneha M.; Radhakrishnan, Aneesha; Nanjappa, Vishalakshi; Kumar, Manish; Raja, Remya; Patil, Arun H.; Kumari, Anjali; Manoharan, Malini; Coral, Karunakaran; Murugan, Saktivel; Prasad, T. S. Keshava; Chang, Xiaofei; Mathur, P. B.; Kumar, Prashant; Gupta, Ravi; Gupta, Rohit; Khanna-Gupta, Arati; Sidransky, David; Chatterjee, Aditi; Gowda, Harsha

doi:10.1038/s41598-019-55208-5

Cited by 15 publications

(7 citation statements)

References 74 publications

(73 reference statements)

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“…Accordingly, pathway analysis indicated that the targets of each herb in YWLS were enriched in these signaling pathways. We found that increased expression of 42 genes was associated with decreased survival, which was consistent with previous evidence, such as EGFR, AKT1, SERPINE1, HSP90AA1, HSP90B1 (Fan et al, 2020), PLAU (Li et al, 2021), MAP2K1 (Jain et al, 2019), and CCND1 (Feng et al, 2011). Among these survival-related genes, 33 genes had higher expression in tumor tissues than in normal tissues like EGFR, AKT1, and HSP family genes, suggesting they could serve as diagnostic markers to distinguish normal from tumoral samples.…”

Section: Discussionsupporting

confidence: 90%

“…Dual inhibition of EGFR and MAPK/CDK4/6 prevented oesophageal squamous cell carcinoma (OSCC) progression (Zhou et al, 2017). Therapeutic targeting of MAP2K1 in the MAPK pathway was a promising strategy for EGFR inhibitor (erlotinib)-resistant HNSCC patients (Jain et al, 2019). It was reported that Aurora kinases were potential targets to overcome EGFR inhibitor resistance in HNSCC, indicating that Aurora kinase A (AURKA) blockade might be a promising approach (Kim and Bandyopadhyay, 2021).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Molecular Targets and Potential Mechanisms of Yinchen Wuling San Against Head and Neck Squamous Cell Carcinoma by Network Pharmacology and Molecular Docking

et al. 2022

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Head and neck squamous cell carcinoma (HNSCC) represents one of the most malignant and heterogeneous tumors, and the patients have low 5-year survival. Traditional Chinese medicine (TCM) has been demonstrated as an effective complementary and/or alternative therapy for advanced malignancies including HNSCC. It has been noted that several herbs that are used for preparing Yinchen Wuling San (YWLS) have anti-tumor activities, whereas their mechanisms of action remain elusive. In this study, network pharmacology and molecular docking studies were employed to explore the underlying mechanisms of action of YWLS against HNSCC. The 58 active ingredients from six herbs used for YWLS and their 506 potential targets were screened from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. A total of 2,173 targets associated with HNSCC were mainly identified from the DisGeNET and GeneCards databases. An active components-targets-disease network was constructed in the Cytoscape. Top 20 hub targets, such as AKT1, EGFR, TNF, ESR1, SRC, HSP90AA1, MAPK3, ERBB2, and CCND1, were identified by a degree in the protein–protein interaction (PPI) network. Gene functional enrichment analysis showed that PI3K-AKT, MAPK, Ras, TNF, and EGFR were the main signaling pathways of YWLS in treating HNSCC. There were 48 intersected targets such as EGFR, AKT1, and TNF that were associated with patients’ outcomes by the univariate Cox analysis, and most of them had increased expression in the tumor as compared to normal tissues. The area under curves of receiver operating characteristic indicated their diagnostic potential. Inhibition of these survival-related targets and/or combination with EGFR or AKT inhibitors were promising therapeutic options in HNSCC. The partial active components of YWLS exhibited good binding with the hub targets, and ADME analysis further evaluated the drug-likeness of the active components. These compounds and targets identified in this study might provide novel treatment strategies for HNSCC patients, and the subsequent work is essential to verify the underlying mechanisms of YWLS against HNSCC.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Identification of Molecular Targets and Potential Mechanisms of Yinchen Wuling San Against Head and Neck Squamous Cell Carcinoma by Network Pharmacology and Molecular Docking

et al. 2022

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“…It thereby inhibits receptor autophosphorylation and blocks downstream signals 16 . Erlotinib is used in treatment of different types of cancer as lung cancer 17 and head and neck squamous cell carcinoma 18 . Many studies showed beneficial effects of erlotinib in different kidney injuries.…”

Section: Introductionmentioning

confidence: 99%

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Awad

Saleh

Abu-Elsaad

et al. 2020

Sci Rep

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Renal fibrosis is a failed regenerative process that facilitates chronic kidney disease progression. The current study was designed to study the effect of erlotinib, a receptor tyrosine kinase inhibitor, on the progression of renal fibrosis. The study included four groups of mice: control group; adenine group: received adenine (0.2% w/w) daily with food for 4 weeks; erlotinib group: received 80 mg/ kg/day erlotinib orally (6 ml/kg/day, 1.3% w/v suspension in normal saline 0.9%) for 4 weeks; adenine + erlotinib group: received adenine and erlotinib concurrently. Kidney function and antioxidant biomarkers were measured. Renal expression of Bcl2 and p53 and histopathological changes (tubular injury and renal fibrosis) were scored. Renal tissue levels of transforming growth factor-β 1 , p-ERK1/2 and p-STAT3 were measured. Results obtained showed significant decrease (P < 0.001) in serum creatinine, urea and uric acid in erlotinib + adenine group. Level of malondialdehyde was decreased significantly (P < 0.001) while reduced glutathione and catalase levels were increased (P < 0.01) by erlotinib concurrent administration. Erlotinib markedly reduced fibrosis and tubular injury and decreased TGF-β1, p-ERK1/2 and p-STAT3 (P < 0.5). In addition, expression level of Bcl-2 was elevated (P < 0.001) while that of p53-was reduced compared to adenine alone. Erlotinib can attenuate renal fibrosis development and progression through anti-fibrotic, antioxidant and antiapoptotic pathways. Chronic kidney disease (CKD) is a global health burden and is considered as an independent risk factor for cardiovascular diseases. Its prevalence is correlated to many health problems as diabetes, hypertension and obesity 1, 2. Renal fibrosis is a failed regenerative process that facilitates the development of CKD. The progression of renal insufficiency in patients with CKD is mainly due to tubulointerstitial fibrosis, glomerular inflammation and tubular atrophy 3. Many cellular events are involved in tubulointerstitial fibrosis as infiltration of inflammatory cells, fibroblast activation, extracellular matrix (ECM) deposition and microvascular rarefaction 4. Various mediators are involved in the development of CKD and may represent possible targets for therapy such as transforming growth factor (TGF)-β, nuclear factor-erythroid 2 related factor, peroxisome proliferatoractivated γ receptor, IL-11 and advanced glycation endproducts 5, 6. Recently, studies reported involvement of miRNA in the progression of CKD progression 7. Tyrosine kinases have a pivotal role in cell signalling, and their activity deregulation can promote the development and progression of fibrotic diseases. As a result, pathologic activation of tyrosine kinases can drive fibrogenesis 8. Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, has been identified in renal tissue mainly in the epithelial cells of distal and collecting tubules, peritubular vessels and glomeruli with more abundant expression in diseased than in normal kidneys 9, 10. Activation of these r...

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“…EMT is a dynamic change in cellular architecture that leads to changes in cell migration and invasion. Its role has been well documented in developmental process and closely associated with tumor dissemination and metastasis [ 43 , 44 ]. Several genetic, epigenetic, and proteomic regulators are known to coordinate this highly complex process.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer quantitation of epithelial-mesenchymal transition dynamics using parallel reaction monitoring-based targeted proteomics approach

et al. 2022

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Epithelial–mesenchymal transition (EMT) is a dynamic and complex cellular process that is known to be hijacked by cancer cells to facilitate invasion, metastasis and therapeutic resistance. Several quantitative measures to assess the interplay between EMT and cancer progression are available, based on large scale genome and transcriptome data. However, these large scale multi-omics studies have repeatedly illustrated a lack of correlation in mRNA and protein abundances that may be influenced by diverse post-translational regulation. Hence, it is imperative to understand how changes in the EMT proteome are associated with the process of oncogenic transformation. To this effect, we developed a parallel reaction monitoring-based targeted proteomics method for quantifying abundances of EMT-associated proteins across cancer cell lines. Our study revealed that quantitative measurement of EMT proteome which enabled a more accurate assessment than transcriptomics data and revealed specific discrepancies against a backdrop of generally strong concordance between proteomic and transcriptomic data. We further demonstrated that changes in our EMT proteome panel might play a role in tumor transformation across cancer types. In future, this EMT panel assay has the potential to be used for clinical samples to guide treatment choices and to congregate functional information for the development and advancing novel therapeutics.

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MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma

Cited by 15 publications

References 74 publications

Identification of Molecular Targets and Potential Mechanisms of Yinchen Wuling San Against Head and Neck Squamous Cell Carcinoma by Network Pharmacology and Molecular Docking

Identification of Molecular Targets and Potential Mechanisms of Yinchen Wuling San Against Head and Neck Squamous Cell Carcinoma by Network Pharmacology and Molecular Docking

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Pan-cancer quantitation of epithelial-mesenchymal transition dynamics using parallel reaction monitoring-based targeted proteomics approach

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