Linked Life Data

21487605

Source:http://linkedlifedata.com/resource/pubmed/id/21487605

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pubmed-article:21487605pubmed:abstractTextErbB2 is frequently activated in tumors, and influences a wide array of cellular functions, including proliferation, apoptosis, cell motility and adhesion. HKI-272 (neratinib) is a small molecule pan-kinase inhibitor of the ErbB family of receptor tyrosine kinases, and shows strong antiproliferative activity in ErbB2-overexpressing breast cancer cells. We undertook a genome-wide pooled lentiviral RNAi screen to identify synthetic lethal or enhancer (synthetic modulator screen) genes that interact with neratinib in a human breast cancer cell line (SKBR-3). These genes upon knockdown would modulate cell viability in the presence of subeffective concentrations of neratinib. We discovered a diverse set of genes whose depletion selectively impaired or enhanced the viability of SKBR-3 cells in the presence of neratinib. We observed diverse pathways including EGFR, hypoxia, cAMP, and protein ubiquitination that, when co-treated with RNAi and neratinib, resulted in arrest of cell proliferation. Examining the changes of these genes and their protein products also led to a rationale for clinically relevant drug combination treatments. Treatment of cells with either paclitaxel or cytarabine in combination with neratinib resulted in a strong antiproliferative effect. The identification of novel mediators of cellular response to neratinib and the development of potential drug combination treatments have expanded our understanding of neratinib's mode-of-action for the development of more effective therapeutic regimens. Notably, our findings support a paclitaxel and neratinib phase III clinical trial in breast cancer patients.lld:pubmed
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pubmed-article:21487605pubmed:articleTitleA genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments.lld:pubmed
pubmed-article:21487605pubmed:affiliationSystems Biology, Global Biotherapeutics, Pfizer Inc., 87 Cambridgepark Drive, Cambridge, MA 02140, USA. attila.seyhan@pfizer.comlld:pubmed
pubmed-article:21487605pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:21487605pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed