Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic

Cell Reports
Benjamin D Levine, Ross L Cagan

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.

References

Sep 19, 1998·Developmental Biology·W Y ParkW V Cardoso
May 12, 2001·Cell·B A Edgar, T L Orr-Weaver
Feb 13, 2004·Developmental Cell·Ana C Santos, Ruth Lehmann
Mar 31, 2005·Seminars in Cell & Developmental Biology·Viravuth P Yin, Carl S Thummel
Oct 4, 2005·Developmental Biology·Arjun Guha, Thomas B Kornberg
Dec 6, 2005·Developmental Cell·Clemens Cabernard, Markus Affolter
Feb 3, 2006·Cancer Research·Kathryn E O'ReillyNeal Rosen
Jun 23, 2007·Nature Reviews. Drug Discovery·Panagiotis A KonstantinopoulosAthanasios G Papavassiliou
Jun 23, 2009·Biochemical Pharmacology·Oras Mistafa, Ulla Stenius
Jul 2, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Klaus P HoeflichMark R Lackner
Sep 26, 2009·Developmental Biology·Deborah J Andrew, Andrew J Ewald
Oct 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Anthony C FaberJeffrey A Engelman
Apr 21, 2010·Respiratory Physiology & Neurobiology·Matthias Behr
Dec 1, 2011·Advances in Experimental Medicine and Biology·Thomas RoederChristina Wagner
Jan 31, 2012·International Journal of Cancer. Journal International Du Cancer·Altaf MohammedChinthalapally V Rao
Sep 11, 2012·Nature·UNKNOWN Cancer Genome Atlas Research Network
Aug 27, 2013·Biochemical and Biophysical Research Communications·Yeon Hee ParkYoung-Hyuck Im
Sep 27, 2014·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Thomas E Stinchcombe, Gary L Johnson
Jun 30, 2015·Cell·Cathy SlackLinda Partridge

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Citations

Jun 15, 2016·Trends in Pharmacological Sciences·Amarish Kumar YadavSubash Chandra Gupta
Sep 9, 2016·Disease Models & Mechanisms·Susumu Hirabayashi
Jul 19, 2018·International Journal of Molecular Sciences·Nathan Powers, Ajay Srivastava
Jan 20, 2018·Endocrine-related Cancer·Tirtha K Das, Ross L Cagan
May 6, 2019·Wiley Interdisciplinary Reviews. Developmental Biology·Tin Tin Su
Oct 1, 2019·PLoS Genetics·Sol FereresThomas B Kornberg
May 30, 2020·International Journal of Molecular Sciences·Erdem Bangi
Jun 20, 2020·Genome Génome / Conseil National De Recherches Canada·Cassandra Millet-BoureimaChiara Gamberi
Sep 1, 2020·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Min ZhangYoshinobu Nakanishi
Sep 4, 2019·Disease Models & Mechanisms·Ketu Mishra-GorurTian Xu
Aug 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Tianyi ZhangJun-Yuan Ji
Apr 26, 2018·BioMed Research International·Helena E Richardson, Marta Portela
Jul 25, 2019·American Journal of Clinical Oncology·Ali Fatehi Hassanabad, Susan A McBride
Mar 2, 2019·Disease Models & Mechanisms·Julija Hmeljak, Monica J Justice
Mar 19, 2019·Frontiers in Genetics·Zhasmine MirzoyanPaola Bellosta
Oct 2, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jorge Iván Castillo-QuanLinda Partridge
Aug 23, 2020·International Journal of Molecular Sciences·Helena E RichardsonDaniela Grifoni
Jan 6, 2017·ILAR Journal·Kevin Strange
Oct 21, 2020·British Journal of Pharmacology·Julio BuñayJean-Marc A Lobaccaro
Jun 21, 2019·Molecular Cancer Therapeutics·Judith BossenThomas Roeder
Dec 5, 2020·Cancer Science·Ryodai YamamuraMasahiro Sonoshita
Jan 31, 2021·Communications Biology·Briana RackleyMelissa Gilbert-Ross

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