What is Chemical Genomics?
Cell-permeable chemical ligands are particularly useful in systematic genomic approaches to study important cellular mechanisms. Chemical genomics is the development of target-specific ligands and the use of chemical libraries to investigate global gene and protein functions [1].
An outline of a genetic screen is illustrated in the graphic to the right. Cell cultures and chemicals can be tested together in an array of combinations. Knowing the genetic background of cells can direct experiments to show the sufficiency or necessity of molecular functions. Testing for phenotypes in this genetic screens can be accomplished in diverse and created ways: cells can be stained and imaged or probed for specific molecules.
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Compiling information on potentially useful chemicals can broaden the applications of chemical genomics in disease prognosis and treatment. For the EGFR gene, there are several small molecules that can inhibit EGFR signaling and give insight into cellular function.
Results
A Bioassay search on Pubmed yielded the example shown above, where HaCat cells were exposed to certain chemicals and potential drugs. HaCat cells have been extensively used to study the epidermal homeostasis which make them useful lung cancer models [2]. The discovery of covalent inhibitors of oncogenes can be used to study normal cellular function important to regular lung function.
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Tyrosine Kinase inhibitors are amongst the most common anti-cancer agents for LADC. Amongst these TKIs, there are “erlotinib” and “gefitinib”, both worth mentioning could serve as tumor-specific inhibitors [2]. Studying EGFR mutations in model organisms could provide a potential model for clinical applications of TKIs.
When traversing the "Tested Substances" listed above, a similar table to the left will appear. The image shows chemicals that've been used to screen Epidermal cells [3]. The first molecule is Osimertinib, which is a commonly researched TKI. To investigate these chemicals, visit Pubchem which contains to the identity of the molecules by ID number or associated research.
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Discussion
Quantifying the effects of exogenous ligands on cell proliferation and migration between wild type and mutant mice will illustrate how prevalent tyrosine dependent function is for these phenotypes. It may be possible that chemical disruption of loss of function tyrosine kinase mutant cells will affect alternative mechanisms of increased cell proliferation and migration.
Zebrafish models were treated with the one of the TKIs shown above. GFP and RFP probes display different protein expression. This is an interesting example of the uses of Afatinib to study neuromast, or sensory epithelial tissue growth [4]. Fluorescent probes illustrate how this drug affects this type of growth.
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One last interesting point is that Tyrosine Kinase Inhibitors don't only interact with the Tyrosine Kinase domain [5]. This could have some implications in clinical uses of this drug and its affects on cancer-associated gene expression.
References
1.) Gavin MacBeath, Chemical genomics: what will it take and who gets to play? (2001). Retrieved from: https://genomebiology.biomedcentral.com/articles/10.1186/gb-2001-2-6-comment2005
2.) Coldren, Helfrich, et al., Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines, 2006. Retrieved from: https://mcr.aacrjournals.org/content/4/8/521.long
3.) Christophe, Antczak,et al., Domain-Based Biosensor Assay to Screen for Epidermal Growth Factor Receptor Modulators in Live Cells. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277729/
4.) Rethink of EGFR in Cancer With Its Kinase Independent Function on Board. Thomas R1, Weihua Z1. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/31508364
2.) Coldren, Helfrich, et al., Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines, 2006. Retrieved from: https://mcr.aacrjournals.org/content/4/8/521.long
3.) Christophe, Antczak,et al., Domain-Based Biosensor Assay to Screen for Epidermal Growth Factor Receptor Modulators in Live Cells. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277729/
4.) Rethink of EGFR in Cancer With Its Kinase Independent Function on Board. Thomas R1, Weihua Z1. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/31508364