%0 Journal Article
%T Determination of the Proteomic Response To Lapatinib Treatment Using A Comprehensive and Reproducible Ion-current-based Proteomics Strategy - Determination of the Proteomic Response To Lapatinib Treatment Using A Comprehensive and Reproducible Ion-current-based Proteomics Strategy - Open Access Pub
%A Fiona O¡¯Neill
%A Frank Engler
%A Jun Li
%A Jun Qu
%A Kathleen O¡¯Connell
%A Kim Hennessy
%A Robert M. Straubinger
%A Robert O¡¯Connor
%J OAP | Home | Journal of Proteomics and Genomics Research | Open Access Pub
%D 2018
%X Lapatinib, a small molecule tyrosine kinase inhibitor is currently used in the treatment of HER2-positive breast cancer. The aim of this study was to further understanding of lapatinib response for the development of novel treatment lapatinib-focussed treatment strategies. HER2-overexpressing SKBR3 breast cancer cells were treated with lapatinib for 12 hours and the resultant proteome analyzed by a comprehensive ion-current-based LC-MS strategy. Among the 1224 unique protein identified from SKBR3 cell lysates, 67 showed a significant change in protein abundance in response to lapatinib. Of these, CENPE a centromeric protein with increased abundance, was chosen for further validation. Knockdown and inhibition of CENPE demonstrated that CENPE enhances SKBR3 cell survival in the presence of lapatinib. Based on this study, CENPE inhibitors may warrant further investigation for use in combination with lapatinib. DOI 10.14302/issn.2326-0793.jpgr-13-257 HER2, a member of the Human Epidermal growth factor Receptor (HER) family, is overexpressed in approximately 25% of breast cancers, resulting in the constitutive activation of tyrosine kinase signalling driving tumour cell growth 1. This plays a crucial role in cancer pathogenesis and is associated with increased tumour invasiveness and poor prognosis 2, 3, 4. Lapatinib (GW572016, GlaxoSmithKline Kline, Research Triangle Park, NC), acts as a dual tyrosine kinase inhibitor of EGFR and HER-2 competing with adenosine triphosphate for its binding site on these receptors. This inhibits phosphorylation of EGFR and HER2, with downstream effects on cell survival and proliferation 5. In 2007, the US FDA approved lapatinib in combination with capecitabine for second line treatment of HER2-positive breast cancer patients 6. Proteomics has been used to identify different breast cancer subtypes 7, 8, and to identify HER2 signalling proteins 9. Genomic profiles of lapatinib response in breast cancer have been carried out, however, no proteomic studies have been published to date 10, 11. Characterisation of cellular responses to lapatinib may have significant importance for the identification of markers of lapatinib response and to identify potential drug targets made available by lapatinib treatment thereby improving efficacy. Identification of drug-responsive proteins via proteomics approaches remains highly challenging, due to the wide dynamic range of a typical cellular proteome and the fact that most regulatory proteins are of lower abundance 12, 13. In order to achieve high proteomic coverage and accurate
%U https://www.openaccesspub.org/jpgr/article/50