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Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic
Benjamin D Levine1, Ross L Cagan1
1Department of Developmental and Regenerative Biology and the Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029-1020, USA.
Abstract:
We have developed a Drosophila lung cancer model by targeting Ras1(G12V)--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.
Insights
A new Drosophila lung cancer model identified trametinib and fluvastatin as promising drugs. Combining these FDA-approved medications synergistically reduced tumor formation and improved survival in flies and human cells.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- The Ras/MAPK and PI3K/AKT pathways are frequently dysregulated in lung cancer.
- Developing effective therapeutic strategies for lung adenocarcinoma remains a significant challenge.
Purpose of the Study:
- To establish a Drosophila melanogaster model for lung cancer research.
- To screen FDA-approved drugs for efficacy in this model.
- To investigate the therapeutic potential of combining MEK and HMG-CoA reductase inhibitors.
Main Methods:
- Development of a Drosophila tracheal system model expressing Ras1(G12V) and/or PTEN knockdown.
- Screening of FDA-approved drugs to identify compounds enhancing animal survival.
- Pharmacological evaluation of trametinib (MEK inhibitor) and fluvastatin (HMG-CoA reductase inhibitor).
- Assessment of drug effects on signaling pathways (Ras, PI3K) and protein prenylation.
- Testing drug combinations in the Drosophila model and human A549 lung adenocarcinoma cells.
Main Results:
- Targeting Ras1(G12V) in the Drosophila trachea induced tumor-like growths and lethality.
- Trametinib and fluvastatin administration improved animal survival.
- Fluvastatin inhibited Ras and PI3K pathway activity and protein prenylation.
- Drug combination demonstrated synergistic tumor suppression and lethality rescue in flies and human cells.
- Fluvastatin mitigated trametinib toxicity in vivo.
Conclusions:
- The Drosophila lung cancer model is a valuable tool for drug discovery.
- Combining statins (like fluvastatin) with MAPK inhibitors (like trametinib) shows synergistic efficacy.
- This combination may improve the therapeutic index for lung adenocarcinoma treatment.
- Fluvastatin exhibits dual action, directly impacting tumor cells and reducing drug toxicity.
