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Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer.

Applied Bioinformatics of Cancer's picture
TitleDefining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer.
Publication TypeJournal Article
Year of Publication2012
AuthorsSims, AH, Zweemer, AJM, Nagumo, Y, Faratian, D, Muir, M, Dodds, M, Um, I, Kay, C, Hasmann, M, Harrison, DJ, Langdon, SP
JournalBr J Cancer
Volume106
Issue11
Pagination1779-89
Date Published2012 May 22
ISSN1532-1827
KeywordsAnimals, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Blotting, Western, Female, Gene Expression, Gene Expression Profiling, Humans, Mice, Mice, Nude, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Xenograft Model Antitumor Assays
Abstract

BACKGROUND: Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, the downstream signalling to explain how these drugs mediate their response is not clearly understood.

METHODS: Transcriptome profiling was performed after 4 days of trastuzumab, pertuzumab and combination treatment in human ovarian cancer in vivo. Signalling pathways identified were validated and investigated in primary ovarian xenografts at the protein level and across a timeseries.

RESULTS: A greater number and variety of genes were differentially expressed by the combination of antibody therapies compared with either treatment alone. Protein levels of cyclin-dependent kinase inhibitors p21 and p27 were increased in response to both agents and further by the combination; pERK signalling was inhibited by all treatments; but only pertuzumab inhibited pAkt signalling. The expression of proliferation, apoptosis, cell division and cell-cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting the heterogeneity of response in ovarian cancer and a need to establish predictive biomarkers.

CONCLUSION: This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo highlights both common and distinct downstream effects to agents used alone or in combination, suggesting that complementary pathways may be involved.

DOI10.1038/bjc.2012.176
Alternate JournalBr. J. Cancer
PubMed ID22549178
PubMed Central IDPMC3364568

Comments

Applied Bioinformatics of Cancer's picture

This paper is the first to comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo.

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