An EGFR-InducedDrosophilaLung Tumor Model Identifies Alternative Combination Treatments

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 (EGFR CA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFR CA 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 EGFRinduced 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.

A Personalized Therapeutics Approach Using an In Silico Drosophila Patient Model Reveals Optimal Chemo- and Targeted Therapy Combinations for Colorectal Cancer

“…As a result, over 50 different data repositories, and tools are now available for hosting data on the fly genome, RNAi screens, and expression data including FlyGut-seq (28), and FlyAtlas (29) databases. Specifically in the case of cancer, several in vivo studies have been designed to elicit novel therapeutic targets using the Drosophila model system (30)(31)(32)(33). One salient example is the validation of indomethacin, which is reported to enhance human Adenomatous Polyposis Coli (hAPC) induced phenotype in Drosophila eye (34) and therefore, employed for treating colorectal cancer (CRC).…”

“…To overcome these issues, multiple therapeutic agents acting on multiple pathways in synergy can significantly increase drug efficacy, besides lowering the therapeutic dosage (36). To evaluate high-efficacy synergistic drug combinations, researchers have employed the Drosophila model in preclinical studies to elicit optimal drug combinations (32,33). The Drosophila Lung Cancer Model by Levine et al (32) helped identify trametinib and fluvastatin as combinatorial drug therapy for lung cancer.…”

In silico Drosophila Patient ModelReveals Optimal Combinatorial Therapies for Colorectal Cancer

“…Specifically in the case of cancer, several in vivo studies have been designed to elicit novel therapeutic targets using Drosophila model system [33][34][35][36][37]. One salient example is the validation of indomethacin, which is reported to enhance human Adenomatous Polyposis Coli (hAPC) induced phenotype in Drosophila eye [38] and therefore, employed for treating colorectal cancer (CRC).…”

“…To overcome these issues, multiple therapeutic agents acting on multiple pathways in synergy can significantly increase drug efficacy, besides lowering the therapeutic dosage [40]. To evaluate potential high-efficacy synergistic drug combinations, researchers have employed Drosophila model in preclinical studies to elicit optimal drug combinations [36,37]. The Drosophila Lung Cancer Model by Levine et al [36] helped identify trametinib and fluvastatin as combinatorial drug therapy for lung cancer.…”

“…The Drosophila Lung Cancer Model by Levine et al [36] helped identify trametinib and fluvastatin as combinatorial drug therapy for lung cancer. Further, an EGFR induced lung tumor model was also designed in Drosophila which assisted in providing an alternative combination of drugs for lung cancer treatment through screening an FDA-approved compound library [37]. However, combinatorial therapies pose unique challenges such as multidrug resistance in chemotherapy [14] and cross drug resistance [41,42] besides the continuing need for higher therapeutic efficacies [43].…”