P1.07-028 Dual Role of the Focal Adhesion Kinase in Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.

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Early Candidate Biomarkers of Non–Small Cell Lung Cancer Are Screened and Identified in Premalignant Lung Lesions

Technology in Cancer Research & Treatment ◽

10.1177/1533034615627391 ◽

2016 ◽

Vol 16 (1) ◽

pp. 66-74 ◽

Cited By ~ 10

Author(s):

Yandong Nan ◽

Jie Du ◽

Lijie Ma ◽

Hua Jiang ◽

Faguang Jin ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Cell Lung Cancer ◽

Src Kinase ◽

Small Cell ◽

Normal Lung ◽

Biological Processes ◽

Small Cell Lung

A specific protein profile that accompanies neoplastic transformation in the premalignant airway epithelium could provide an opportunity for early diagnosis of lung cancer. The aim of this study was to screen and identify early candidate biomarkers of non–small cell lung cancer. Thirteen non–small cell lung cancer samples were obtained within 30 minutes after a surgical resection. Laser capture microdissection was performed to enrich the normal lung cell and squamous metaplasia or atypical adenomatous hyperplasia cell populations. The resulting tandem mass spectrum was automatically searched for proteins against International Protein Index (IPI) human protein database using the TurboSEQUEST searching engine. The molecular function and biological processes of identified proteins were determined based on universal bioinformatics tools. The 2 proteins of interest, focal adhesion kinase and C-terminal Src kinase, were validated using Western blot method. A total of 863 proteins were identified by automatically searching the tandem mass spectrum, among which 427 were dysregulated expression in premalignant airway epithelium compared with those of normal lung cells. The 427 proteins were mainly distributed in 24 sorts of cellular components, 22 molecular function, 15 biological processes, and 10 significant perturbations of pathways. The most significant network included 48 genes and was related to energy production, cell cytoskeleton, cell adhesion, metabolism, oxidative stress, and small molecule biochemistry. Focal adhesion kinase and C-terminal Src kinase were significantly overexpressed in premalignant lung lesion cells compared with the normal lung cells in 13 cases. We identified that there were 427 proteins involved in non–small cell lung cancer carcinogenic process and confirmed the key biological pathways in premalignant lung tissue. The significantly upregulated focal adhesion kinase and C-terminal Src kinase could be considered as molecular biomarkers for early diagnosis and prognosis of non–small cell lung cancer.

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The Prognostic Significance of Focal Adhesion Kinase Expression in Stage I Non–Small-Cell Lung Cancer

Journal of Thoracic Oncology ◽

10.1097/jto.0000000000000248 ◽

2014 ◽

Vol 9 (9) ◽

pp. 1278-1284 ◽

Cited By ~ 11

Author(s):

Grace K. Dy ◽

Lourdes Ylagan ◽

Saraswati Pokharel ◽

Austin Miller ◽

Elizabeth Brese ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Cell Lung Cancer ◽

Prognostic Significance ◽

Small Cell ◽

Small Cell Lung ◽

Focal Adhesion Kinase Expression ◽

Kinase Expression

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G9a promotes invasion and metastasis of non-small cell lung cancer through enhancing focal adhesion kinase activation via NF-κB signaling pathway

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-20-0557 ◽

2020 ◽

pp. molcanres.0557.2020

Author(s):

Ting Sun ◽

Keqiang Zhang ◽

Rajendra P Pangeni ◽

Jun Wu ◽

Wendong Li ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Focal Adhesion Kinase ◽

Signaling Pathway ◽

Focal Adhesion ◽

Cell Lung Cancer ◽

Small Cell ◽

Invasion And Metastasis ◽

Small Cell Lung ◽

Kinase Activation

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Molecular Dynamics of A Biglycan-Rosmarinic Acid Complex with Focal Adhesion Kinase for Possible Arrest of Metastasis in Non-Small Cell Lung Cancer (NSCLC): An In- Silico Study

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v9i4-a.3382 ◽

2019 ◽

Vol 9 (4-A) ◽

pp. 159-166

Author(s):

Hyacinth Highland ◽

Monica Thakur ◽

Pujan Pandya ◽

Archana Mankad ◽

Linz-Buoy George

Keyword(s):

Lung Cancer ◽

Molecular Dynamics ◽

Molecular Docking ◽

Small Cell Lung Cancer ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Cell Lung Cancer ◽

Rosmarinic Acid ◽

Small Cell ◽

Small Cell Lung

Background: Non-small cell lung cancer (NSCLC) is the major cause of mortality all over the world. Significant increase of biglycan is seen in the lung cancer cells when compared with the normal cells. It promotes tumor invasion and metastasis by activating Focal Adhesion Kinase (FAK) signaling pathway. The increased FAK activity may contribute to the metastatic potential of malignant tumors. This study was carried out to establish binding interactions of some selected phytocomponents against biglycan for the possible arrest of metastasis. Methods: Protein-ligand interaction studies were performed using 30 natural compounds from different culinary herbs having potential therapeutic role against the target protein biglycan (BGN). Molegro Virtual Docker (v 5.0) was used as docking tool to evaluate the effectiveness of selected phytocomponents based upon the interaction with the protein’s active site residues with minimal binding energy. Protein-protein docking was performed to observe the interaction of BGN and FAK using Hex (v 8.0.0). Molecular dynamics (10 ns) of BGN-RA-FAK and FAK-RA-BGN was performed in Yasara structure (v 17.8.15) which showed stability of the structure in terms of RMSD values. Results: Molecular docking analysis revealed the selectivity of Rosmarinic acid (RA) towards BGN and FAK. Molecular dynamics trajectory of BGN-RA-FAK and FAK-RA-BGN complexes showed the stability of structure in terms of Time vs Energy and Time vs RMSD values and revealed that binding of RA to BGN will block the interaction of FAK. Conclusions: Hence, investigating the binding interactions of BGN-RA-FAK complex may turn out to be helpful in arresting metastasis in NSCLC. Keywords: Non-small cell lung cancer, Biglycan, Focal adhesion kinase, Phytocomponents, Molecular Docking, Molecular Dynamics

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