Type

Journal Article

Authors

Alex J Eustace
Bryan T Hennessy
Naomi Elster
Aoife Carr
Stephen F Madden
Sinead Toomey
Joyce O'Shaughnessy
Lance Liotta
Virginia Espina
Frankie Holmes
and 4 others

Subjects

Medicine & Nursing

Topics
cancer cells breast cancer mapk signalling cancer cell lines clinical trial lapatinib resistance her2 positive down regulation

A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib. (2016)

Abstract The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an A panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib. Reverse phase protein array (RPPA) was used to determine the effect of refametinib alone and in combination with PI3Ki and HER2-inhibitors on expression and phosphorylation of proteins in the PI3K/AKT and MEK/MAPK pathways. We validated our proteomic Refametinib has anti-proliferative effects when used alone in 2/3 parental HER2-positive breast cancer cell lines (HCC1954, BT474), along with 3 models of these 2 cell lines with acquired trastuzumab or lapatinib resistance (6 cell lines tested). Refametinib treatment led to complete inhibition of MAPK signalling. In HCC1954, the most refametinib-sensitive cell line (IC Refametinib alone or in combination with copanlisib or lapatinib could represent an improved treatment strategy for some patients with HER2-positive breast cancer, and should be considered for clinical trial evaluation. The direct down-regulation of MEK/MAPK but not AKT signalling by HER2 inhibition (e.g. by lapatinib or trastuzumab), which we demonstrate occurs in 18% of HER2-positive breast cancers may serve as a potential biomarker of responsiveness to the MEK inhibitor refametinib.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Alex J Eustace, Bryan T Hennessy, Naomi Elster, Aoife Carr, Stephen F Madden, Sinead Toomey, Joyce O'Shaughnessy, Lance Liotta, Virginia Espina, Frankie Holmes and 4 others

Experts in our system

1
Alex J Eustace
Dublin City University
 
2
Bryan T Hennessy
Royal College of Surgeons in Ireland
Total Publications: 33
 
3
N Elster
Royal College of Surgeons in Ireland
Total Publications: 4
 
4
Aoife Carr
Royal College of Surgeons in Ireland
Total Publications: 8
 
5
Stephen F Madden
Dublin City University
Total Publications: 45
 
6
Sinead Toomey
Royal College of Surgeons in Ireland
Total Publications: 26
 
7
Lance Liotta
Dublin City University
Total Publications: 6
 
8
Virginia Espina
Dublin City University