Cell reports (Cambridge), 2016-02, Vol.14 (6), p.1477-1487
2016
Details
- Autor(en) / Beteiligte
- Titel
- Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic
- Ist Teil von
- Cell reports (Cambridge), 2016-02, Vol.14 (6), p.1477-1487
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2211-1247eISSN: 2211-1247DOI: 10.1016/j.celrep.2015.12.105Titel-ID: cdi_doaj_primary_oai_doaj_org_article_f557198148f04bfca7a82277f5091329
- Format
- –
- Schlagworte
- 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