Comprehensive analysis of tumor NGS data to demonstrate pathways pointing to therapeutic targeting options.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23153-e23153
Author(s):  
Subha Krishnan ◽  
Ally Perlina ◽  
Alex Thomas ◽  
Boyko Kakaradov ◽  
Wayne Delport ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Signaling Pathways ◽  
Tumor Biology ◽  
Comprehensive Analysis ◽  
Complex Nature ◽  
Beta Catenin ◽  
Genomic Alterations ◽  
Genomic Variations ◽  
Downstream Targets ◽  
Therapeutic Decisions

e23153 Background: Recent advancements in NGS technology have enabled precision medicine based on tumor-specific genomic alterations. However, the complex nature of tumor biology demands an integrative analysis of genomic variations to identify converging downstream targets potentially regulated by multiple pathways. Methods: Genomic alterations from whole-genome sequencing results were interpreted in the context of pathways. Beyond listing the implicated known pathways based on genomic alterations, we explored protein interactions cross-linking the pathways to converging downstream targets. An in-house analytical pipeline was used to prioritize candidate pathways from MetaBase™, which contains manually curated pathways and interactions based on published experimental results. Custom pathway diagram was then designed manually to depict the most actionable pathways. The manual review consists of context-checking and addressing the concordant/discordant nature of all interactions. Factor such as mutational impact, directionality, mechanism of interaction and known targeted action are taken into account. Results: Comprehensive analysis of the genomic variations in three tumors types revealed activation of multiple oncogenic signaling pathways. Key events driving the tumor in a melanoma sample were NF1/RAS/MEK/ERK, WNT/beta-catenin pathway, and MITF signaling. Three interconnected signaling pathways, WNT, PI3K/AKT, and P53 were impacted by genomic alterations in a colorectal sample, which point to activation of converging downstream targets- CDK6, VEGFA, and COX-2. Integrated discovery of genomic alterations in an esophageal adenocarcinoma sample suggested potential activation of PI3K/AKT/MTOR and p16/Cyclin D1/CDK pathways. This could synergistically activate downstream converging targets- VEGFA, Cyclin D1, CDK6, CDK4, AURKA; some of which also showed relative RNA overexpression, supporting our pathway findings. Conclusions: Comprehensively analyzing the genomic alterations in context of cell signaling pathways provides us insights on how the pathways synergistically affect downstream targetable events, which in turn can impact therapeutic decisions.

Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

2020 ◽  
Vol 26 (15) ◽  
pp. 1729-1741 ◽  
Author(s):  
Seyed H. Shahcheraghi ◽  
Venant Tchokonte-Nana ◽  
Marzieh Lotfi ◽  
Malihe Lotfi ◽  
Ahmad Ghorbani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Chemotherapy Resistance ◽  
Wnt Signaling Pathway ◽  
Therapeutic Interventions ◽  
Beta Catenin ◽  
Clinical Prognosis ◽  
Invasion And Migration ◽  
And Migration

: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM’s invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽  
2020 ◽  
Author(s):  
Qijie Zhao ◽  
Jinan Guo ◽  
Yueshui Zhao ◽  
Jing Shen ◽  
Parham Jabbarzadeh Kaboli ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Comprehensive Analysis ◽  
The Cancer Genome Atlas ◽  
Gastrointestinal Cancers ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

2021 ◽  
pp. 1-15
Author(s):  
Ping Xu ◽  
Xiao Mo ◽  
Ruixue Xia ◽  
Long Jiang ◽  
Chengfei Zhang ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Lung Adenocarcinoma ◽  
Potassium Channel ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Biology ◽  
Erk Signaling ◽  
Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

scholarly journals Systematic identification of cancer driving signaling pathways based on mutual exclusivity of genomic alterations

2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Özgün Babur ◽  
Mithat Gönen ◽  
Bülent Arman Aksoy ◽  
Nikolaus Schultz ◽  
Giovanni Ciriello ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Mutual Exclusivity ◽  
Genomic Alterations ◽  
Systematic Identification

Heterogeneity Within Molecular Subtypes of Breast Cancer

2021 ◽  
Author(s):  
Kevin M. Turner ◽  
Syn Kok Yeo ◽  
Tammy M Holm ◽  
Elizabeth Shaughnessy ◽  
Jun-Lin Guan
Keyword(s):  
Breast Cancer ◽  
Molecular Subtypes ◽  
Tumor Biology ◽  
Treatment Resistance ◽  
Intratumoral Heterogeneity ◽  
Molecular Heterogeneity ◽  
Improve Treatment ◽  
Therapeutic Decisions ◽  
Single Tumor

Breast cancer is the quintessential example of how molecular characterization of tumor biology guides therapeutic decisions. From the discovery of the estrogen receptor to current clinical molecular profiles to evolving single cell analytics, the characterization and compartmentalization of breast cancer into divergent subtypes is clear. However, competing with this divergent model of breast cancer is the recognition of intratumoral heterogeneity, which acknowledges the possibility that multiple different subtypes exist within a single tumor. Intratumoral heterogeneity is driven by both intrinsic effects of the tumor cells themselves as well as extrinsic effects from the surrounding microenvironment. There is emerging evidence that these intratumoral molecular subtypes are not static; rather, plasticity between divergent subtypes is possible. Inter-conversion between seemingly different subtypes within a tumor drives tumor progression, metastases, and treatment resistance. Therapeutic strategies must therefore contend with changing phenotypes in an individual patient's tumor. Identifying targetable drivers of molecular heterogeneity may improve treatment durability and disease progression.

Expression of non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 in relation to patient outcome in human colon adenocarcinomas

Apmis ◽  
2004 ◽  
Vol 112 (1) ◽  
pp. 49-56 ◽  
Author(s):  
JOHAN BONDI ◽  
GEIR BUKHOLM ◽  
JAHN M. NESLAND ◽  
IDA R. K. BUKHOLM
Keyword(s):  
Patient Outcome ◽  
Cyclin D1 ◽  
Human Colon ◽  
Beta Catenin

scholarly journals Association of different patterns of expression of beta-catenin and cyclin D1 with pathogenesis of breast carcinoma

2020 ◽  
Vol 63 (1) ◽  
pp. 13
Author(s):  
Kachnar Varma ◽  
Aprajita Chauhan ◽  
Mudita Bhargava ◽  
Vatsala Misra ◽  
Sapan Srivastava
Keyword(s):  
Breast Carcinoma ◽  
Cyclin D1 ◽  
Beta Catenin

Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction

1999 ◽  
Vol 112 (24) ◽  
pp. 4485-4489 ◽  
Author(s):  
C. Wu
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Adaptor Protein ◽  
Small Gtpase ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Integrin Linked Kinase

Integrin-linked kinase (ILK) is a focal adhesion serine/threonine protein kinase that is emerging as a key signaling protein functioning at one of the early convergence points of integrin- and growth factor-signaling pathways. ILK binds to PINCH through the N-terminal ankyrin (ANK) repeat domain and the PINCH binding is crucial for focal adhesion localization of ILK. The ILK-PINCH interaction also connects ILK to Nck-2, an SH2-SH3-containing adaptor protein that interacts with components of growth factor and small GTPase signaling pathways. The kinase activity of ILK is regulated by both cell adhesion and growth factors in a phosphoinositide 3-kinase (PI3K)-dependent manner. ILK phosphorylates downstream targets such as protein kinase B (PKB, also known as Akt) and glycogen synthase kinase 3 (GSK-3) and regulates their activities. Overexpression of ILK in epithelial cells leads to striking morphological changes mimicking epithelial-mesenchymal transition, including upregulation of integrin-mediated fibronectin matrix assembly and downregulation of cell-cell adhesions. Furthermore, ILK regulates nuclear translocation of (beta)-catenin and gene expression, and promotes cell cycle progression and tumor formation. Recent genetic studies in Drosophila melanogaster and Caenorhabditis elegans have shown that lack of expression of ILK or PINCH results in phenotypes resembling those of integrin-null mutants, which demonstrates that ILK and PINCH are indispensable for integrin function during embryonic development.

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