Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic

• Published in: Cell reports (Cambridge) 2016-02, Vol.14 (6), p.1477-1487
• Main Authors: Levine, Benjamin D., Cagan, Ross L.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Disease Models, Animal; Drosophila; Drosophila melanogaster - drug effects; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - antagonists & inhibitors; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Drug Combinations; Drug Screening Assays, Antitumor - methods; Drug Synergism; Fatty Acids, Monounsaturated - pharmacology; Fluvastatin; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; IMP Dehydrogenase - antagonists & inhibitors; IMP Dehydrogenase - genetics; IMP Dehydrogenase - metabolism; Indoles - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; non-small-cell lung cancer; Protein Kinase Inhibitors - pharmacology; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Pyridones - pharmacology; Pyrimidinones - pharmacology; Signal Transduction; Survival Rate; trachea; trametinib
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.12.105

We have developed a Drosophila lung cancer model by targeting Ras1G12V—alone or in combination with PTEN knockdown—to the Drosophila tracheal system. This led to overproliferation of tracheal tissue, formation of tumor-like growths, and animal lethality. Screening a library of FDA-approved drugs identified several that improved overall animal survival. We explored two hits: the MEK inhibitor trametinib and the HMG-CoA reductase inhibitor fluvastatin. Oral administration of these drugs inhibited Ras and PI3K pathway activity, respectively; in addition, fluvastatin inhibited protein prenylation downstream of HMG-CoA reductase to promote survival. Combining drugs led to synergistic suppression of tumor formation and rescue lethality; similar synergy was observed in human A549 lung adenocarcinoma cells. Notably, fluvastatin acted both within transformed cells and also to reduce whole-body trametinib toxicity in flies. Our work supports and provides further context for exploring the potential of combining statins with MAPK inhibitors such as trametinib to improve overall therapeutic index. [Display omitted] •A Drosophila Ras-Pten lung cancer model was established•Altering cancer genes in the trachea led to growth and migration defects•Screening identified trametinib plus fluvastatin as a candidate therapeutic cocktail•Trametinib/fluvastatin showed synergistic efficacy in human lung cancer cell line Levine and Cagan describe an oncogenic Ras-driven lung cancer model in Drosophila that is used in a whole-animal drug screen of over 1,000 FDA-approved compounds. Two hits, the MEK inhibitor trametinib and the statin fluvastatin, synergized to rescue oncogenic phenotypes and lethality.