Absence ofc-Kit and members of the epidermal growth factor receptor family in refractory germ cell cancer

Epidermal Growth Factor Receptor (EGFR) is still the main target of the Head and Neck Squamous Cell Cancer (HNSCC) because its overexpression has been detected in more than 90% of this type of cancer. This overexpression is usually linked with more aggressive disease, increased resistance to chemotherapy and radiotherapy, increased metastasis, inhibition of apoptosis, promotion of neoplastic angiogenesis, and, finally, poor prognosis and decreased survival. Due to this reason, the main target in the search of new drugs and inhibitors candidates is to downturn this overexpression. Quantitative Structure-Activity Relationship (QSAR) is one of the most widely used approaches while looking for new and more active inhibitors drugs. In this contest, a lot of authors used this technique, combined with others, to find new drugs or enhance the activity of well-known inhibitors. In this paper, on one hand, we will review the most important QSAR approaches developed in the last fifteen years, spacing from classical 1D approaches until more sophisticated 3D; the first paper is dated 2003 while the last one is from 2017. On the other hand, we will present a completely new QSAR approach aimed at the prediction of new EGFR inhibitors drugs. The model presented here has been developed over a dataset consisting of more than 1000 compounds using various molecular descriptors calculated with the DRAGON 7.0© software.

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Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.11.890 ◽

2005 ◽

Vol 23 (11) ◽

pp. 2445-2459 ◽

Cited By ~ 505

Author(s):

José Baselga ◽

Carlos L. Arteaga

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Egfr Gene ◽

Epidermal Growth ◽

Egfr Tkis ◽

Receptor Family

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.

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