What are the Signaling Pathway, Diagnostics Marker, Targeted Therapy of Lung Can

Posted by echohan999 on June 24th, 2019

An Introduction to Lung Cancer

As one of the leading causes of cancer death in many industrialized countries, Lung Cancer (LC) claims more than 160,000 and 50,000 lives annually in the America and Japan respectively. The majority of lung cancers, 85% of non-small-cell lung cancer and 98% of small cell lung carcinoma, arise in smokers. Among the 20 kinds of carcinogens in tobacco smoke that link closely the development of lung cancer, polycyclic aromatic hydrocarbons and nicotine-derived nitrosamines are the most significant ones, which lead to gene mutation through the formation of DNA adducts. The formation of adducts results from the metabolic activation of P450 cytochromes, enzymes encoded by CYP gene family and glutathione S-transferase (GSTs) to these carcinogens. Progress in lung cancer biology can contribute to the customized treatment based on specific genes and pathways.

The main signal transduction pathways that can provide therapeutic roadmap include RTK signaling pathway, integrin-mediated pathway and growth inhibition pathway. These networks, in particular cause cell proliferation, apoptosis and vasculogenesis escape. Different between smokers and non-smokers, the genetic and epigenetic pathways concerned about lung tumorigenesis, work as tools for cancer diagnosis, prognosis, clinical follow-up and targeted therapy.

1. Signaling Pathways of Lung Cancer

1.1 RTK signaling cascade. RTKs (Receptor tyrosine kinases) play an important role in the development and regulation of many carcinoid cells.

1.2 Integrin-mediated signaling cascade. Integrins (ITGA/ITGB) are connectors of cell interaction that contribute to cell growth and mitogenesis.

1.3 Growth inhibitory signaling cascade. P53, a sensor of cell stress changing, functions as a transcription factor, for instance DNA damage and oncogenic stimuli.

2. Diagnostics Marker of Lung Cancer

2.1 Molecular markers of lung cancer

Targeted therapy guided by molecular diagnosis is currently the standard treatment for lung cancer patients, which are classified into 3 types – mutation, gene re-arrangement and amplification.

Mutations of molecular markers of LC consist EGFR, KRAS, BRAF, HER2, and MET. Somatic mutations including point substitution, small insertion, and in-frame deletion once activated, are major oncogenic drivers in lung cancer. Discovering activating EGFR mutations and their close relation with the response to EGFR TKIs brings hope to precision medicine. A variety of methods can be used for detecting mutations including direct sequencing, real-time polymerase chain reaction (PCR), and commercial kits.

2.2 Protein Markers

The most universally applied methods for lung cancer diagnosis are chest radiography and computer tomography, which can only identify visible and irreversible changes in lung lobes that call for an urgent need of additional methods for early diagnosis. For the purpose of overcoming the problem, discovering novel, highly sensitive, and specific biomarker become quite crucial. Hence more, accurately identifying the histological type of cancer and respective protein bio-markers is attracting attention. Protein can be regarded as the most suitable bio-marker for lung cancer diagnosis in that they involve in cellular processes.

3. Targeted Therapy of Lung Cancer

Involved in the pathogenesis of lung cancer. various kinds of molecular mechanisms present exciting avenues for target-specific approaches to therapy. The major components of cell signaling pathways, such as RTKs, PKCs, and the MAPK systems, are altered in lung cancer cells by oncogenes through over expression or mutation, and thus result in dysregulated cell signaling and cell proliferation. 

3.1 Lung cancer therapy for RTK pathway

Targeted EGFR: Competitive inhibition of EGFRTK activation by cetuximab and panimab resulted in G1 cell cycle arrest.

Targeted HER-2: Trastuzumab induces growth arrest during G0-G1 phase of cell cycle.

Targeting VEGFR: Bevacizumab is a mAB targeting the receptor of vascular endothelial growth factor-A.

Targeted c-Met: Cabozantinib, a multi-target c-Met inhibitor; Capmatinib is a selective c-Met inhibitor.

Targeted PKC: Kinase inhibitors that work through blocking catalytic sites are not highly specific and can be used as inhibitors of PKC, such as Staurosporine and Bryostatin.

3.2 Lung cancer therapy for integrin-mediated pathway

Matrix metalloproteinases (MMPs) have been implicated in metastasis and angiogenesis, which are a family of enzymes for remodeling of the extracellular matrix in processes of growth and morphogenesis.

Targeting EMC

Targeting integrins

3.3 Lung cancer therapy for growth inhibitory pathway

As a tumor suppressor nuclear phosphoprotein, once the human protein p53 genes are deleted or mutated, cells become susceptible to DNA damage and deregulated cell growth.

Targeting p53

Targeting CDK

Lung cancer, which is also named as lung carcinoma, is marked by uncontrolled cell growth of lung tissue that have two major types, small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), both are malignant lung tumor. The most obvious symptoms are coughing (coughing up blood included), shortness of breath, chest pains and weight loss, etc. New development in the bio-markers of LC could greatly improve the diagnosis and targeting relatively.

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