Type

Journal Article

Authors

Kathy Gately
Stephen P Finn
Sinead Cuffe
Stephen G Maher
Niamh Kelly
Gillian Moore
Paul Dowling
Ken O'Byrne
Susan Heavey
Martin Barr

Subjects

Biochemistry

Topics
lung cancer characterisation cancer cell lines cancer mass spectrometry epithelial mesenchymal transition emt inhibitor mammalian mrna expression panel protein expression cell lines kinase 3

Development and characterisation of a panel of phosphatidylinositide 3-kinase - mammalian target of rapamycin inhibitor resistant lung cancer cell lines. (2018)

Abstract The PI3K-mTOR pathway is involved in regulating all hallmarks of cancer, and is often dysregulated in NSCLC, making it an attractive therapeutic target in this setting. Acquired resistance to PI3K-mTOR inhibition is a major hurdle to overcome in the success of PI3K-mTOR targeted agents. H460, A549, and H1975 resistant cells were generated by prolonged treatment in culture with Apitolisib (GDC-0980), a dual PI3K-mTOR inhibitor over a period of several months, from age-matched parent cells. Resistance was deemed to have developed when a log fold diference in IC50 had been achieved. Resistant cell lines also exhibited resistance to another widely investigated PI3K-mTOR dual inhibitor; Dactolisib (BEZ235). Cell lines were characterised at the level of mRNA (expression array profling expression of >150 genes), miRNA (expression array profling of 2100 miRNAs), protein (bottoms-up label-free mass spectrometry) and phosphoprotein (expression array profling of 84 phospho/total proteins). Key alterations were validated by qPCR and Western blot. H1975 cells were initially most sensitive to Apitolisib (GDC-0980), but developed resistance more quickly than the other cell lines, perhaps due to increased selective pressure from the impressive initial efect. In-depth molecular profling suggested epithelial-mesenchymal transition (EMT) may play a role in resistance to PI3K-mTOR dual inhibition in NSCLC.
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Full list of authors on original publication

Kathy Gately, Stephen P Finn, Sinead Cuffe, Stephen G Maher, Niamh Kelly, Gillian Moore, Paul Dowling, Ken O'Byrne, Susan Heavey, Martin Barr

Experts in our system

1
Kathy Gately
Trinity College Dublin
Total Publications: 22
 
2
Stephen P Finn
Trinity College Dublin
Total Publications: 60
 
3
Sinead Cuffe
Trinity College Dublin
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4
Stephen G Maher
Trinity College Dublin
 
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Niamh Kelly
Trinity College Dublin
 
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Paul Dowling
Maynooth University
Total Publications: 82
 
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Ken O'Byrne
Trinity College Dublin
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Susan Heavey
Trinity College Dublin
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Martin P Barr
Trinity College Dublin
Total Publications: 27