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Alex J Eustace
Bryan T Hennessy
A O'Grady
A Carr
Sinead Toomey
Carys Morgan
Mattia Cremona
N Elster



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A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib. (2015)

Abstract The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80-6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9-29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation.
Collections Ireland -> Royal College of Surgeons in Ireland -> Molecular Medicine Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Molecular Medicine

Full list of authors on original publication

Alex J Eustace, Bryan T Hennessy, A O'Grady, A Carr, Sinead Toomey, Carys Morgan, Mattia Cremona, N Elster

Experts in our system

Alex J Eustace
Dublin City University
Bryan T Hennessy
Royal College of Surgeons in Ireland
Total Publications: 33
Anthony O'Grady
Royal College of Surgeons in Ireland
Total Publications: 35
Aoife Carr
Royal College of Surgeons in Ireland
Total Publications: 8
Sinead Toomey
Royal College of Surgeons in Ireland
Total Publications: 26
Mattia Cremona
Royal College of Surgeons in Ireland
Total Publications: 11