An EGFR-Induced Drosophila Lung Tumor Model Identifies Alternative Combination Treatments.

Judith Bossen,Mandy Mong-Quyen Mai,Michael Spohn,Karin Uliczka,Roxana Pfefferkorn,Iris Bruchhaus,Thomas Roeder,Line Steen,Christine Fink,Holger Heine,Lia Burkhardt

doi:10.1158/1535-7163.mct-19-0168

Abstract

Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFRCA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFRCA induced massive hyper- and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFR-induced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.

Highlights

Lung cancer is the leading cause of cancer-related deaths, with more than 1 million newly diagnosed cases worldwide each year [1]
Somatic mutations in the EGFR gene occur in 10% of all Non–small cell lung cancers (NSCLC) [5]
Experiments were performed on concentrated medium (CM) [5% (w/v) yeast extract (Becton Dickinson), 5% (w/v) sucrose, 8.6% cornmeal, 0.5% (w/v) agar, 0.03% (v/v) propionic acid, 0.3% (v/v) methyl-4-hydroxybenzoate], drug experiments were performed on low-melt CM medium (CM with low-melt agarose)

Summary

Introduction

Lung cancer is the leading cause of cancer-related deaths, with more than 1 million newly diagnosed cases worldwide each year [1]. Non–small cell lung cancers (NSCLC), and in particular adenocarcinomas, account for the majority of all lung cancers. A relatively small number of oncogenic driver mutations are responsible for both the initiation and maintenance of NSCLCs [2,3,4]. One of the most important driver oncogenes in lung cancer is the EGFR. Somatic mutations in the EGFR gene occur in 10% of all NSCLCs [5]. Targeted therapy for patients that carry a mutation in the EGFR gene has been successful, the risk to develop drug resistance during

Methods

Results

Conclusion