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Cell Rep. 2016 Feb 16;14(6):1477-1487. doi: 10.1016/j.celrep.2015.12.105. Epub 2016 Jan 28.

Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic.

Author information

1
Department 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.
2
Department 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. Electronic address: ross.cagan@mssm.edu.

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.

KEYWORDS:

Drosophila; fluvastatin; non-small-cell lung cancer; trachea; trametinib

PMID:
26832408
PMCID:
PMC4904304
DOI:
10.1016/j.celrep.2015.12.105
[Indexed for MEDLINE]
Free PMC Article

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