ena-STUDY-UNIVERSITY OF HAMBURG-13-03-2017-11:35:47:664-375
Specific EGFR inhibitors rescue lethality in a Drosophila model of lung cancer
Lung cancer is still the leading cause of cancer-associated mortality and despite recent promising development, the prognosis is still very poor. To improve the development of novel anti-cancer drugs, we used the fruit fly Drosophila as a favorable and meaningful model. Thus, we are directing ectopic expression of various lung cancer associated oncogenes into the fly's airway epithelium. Expression of these oncogenes induced meta- and hyperplasia of airway epithelial cells, which is characterized by massive structural changes and a strong overproliferation of these epithelial cells. For an in-depth analysis, we focused on the EGFR, as ectopic expression of a constitutively active isoform induced massive hyperplasia, leading to death in early developmental stages presumably due to oxygen deprivation. To evaluate if this lung cancer model is suitable for high-throughput screening approaches, we tested a FDA approved compound library regarding their ability to rescue this lethal phenotype. Only two compounds, the EGFR antagonists afatinib and gefitinib, were able to revert this phenotype and to allow completion of the larval life cycle and formation of pupal stages. Whereas afatinib treatment also rescued the complete development, leading to normal numbers of adult offspring, this number was reduced in gefitinib treated animals implying that treatment interferes with this stage of development. Our study shows that Drosophila is a valuable complement of the toolbox available to develop novel anticancer treatments, as it provides a superb in vivo screening system amenable to high-throughput approaches.
Lung cancer is still the leading cause of cancer-associated mortality and despite recent promising development, the prognosis is still very poor. To improve the development of novel anti-cancer drugs, we used the fruit fly Drosophila as a favorable and meaningful model. Thus, we are directing ectopic expression of various lung cancer associated oncogenes into the fly's airway epithelium. Expression of these oncogenes induced meta- and hyperplasia of airway epithelial cells, which is characterized by massive structural changes and a strong overproliferation of these epithelial cells. For an in-depth analysis, we focused on the EGFR, as ectopic expression of a constitutively active isoform induced massive hyperplasia, leading to death in early developmental stages presumably due to oxygen deprivation. To evaluate if this lung cancer model is suitable for high-throughput screening approaches, we tested a FDA approved compound library regarding their ability to rescue this lethal phenotype. Only two compounds, the EGFR antagonists afatinib and gefitinib, were able to revert this phenotype and to allow completion of the larval life cycle and formation of pupal stages. Whereas afatinib treatment also rescued the complete development, leading to normal numbers of adult offspring, this number was reduced in gefitinib treated animals implying that treatment interferes with this stage of development. Our study shows that Drosophila is a valuable complement of the toolbox available to develop novel anticancer treatments, as it provides a superb in vivo screening system amenable to high-throughput approaches.