Source:http://linkedlifedata.com/resource/pubmed/id/21487605
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
2011-5-16
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| pubmed:abstractText |
ErbB2 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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/ERBB2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/N-(4-(3-chloro-4-(2-pyridinylmethoxy...,
http://linkedlifedata.com/resource/pubmed/chemical/Paclitaxel,
http://linkedlifedata.com/resource/pubmed/chemical/Quinolines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, erbB-2,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
1742-2051
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:volume |
7
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1974-89
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| pubmed:meshHeading |
pubmed-meshheading:21487605-Antineoplastic Agents,
pubmed-meshheading:21487605-Breast Neoplasms,
pubmed-meshheading:21487605-Cell Line, Tumor,
pubmed-meshheading:21487605-Cell Survival,
pubmed-meshheading:21487605-Drug Screening Assays, Antitumor,
pubmed-meshheading:21487605-Drug Synergism,
pubmed-meshheading:21487605-Female,
pubmed-meshheading:21487605-Genes, Neoplasm,
pubmed-meshheading:21487605-Genome-Wide Association Study,
pubmed-meshheading:21487605-Humans,
pubmed-meshheading:21487605-Lentivirus,
pubmed-meshheading:21487605-Oligonucleotide Array Sequence Analysis,
pubmed-meshheading:21487605-Paclitaxel,
pubmed-meshheading:21487605-Quinolines,
pubmed-meshheading:21487605-RNA Interference,
pubmed-meshheading:21487605-Receptor, erbB-2,
pubmed-meshheading:21487605-Recombinant Proteins,
pubmed-meshheading:21487605-Signal Transduction
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| pubmed:year |
2011
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| pubmed:articleTitle |
A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments.
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| pubmed:affiliation |
Systems Biology, Global Biotherapeutics, Pfizer Inc., 87 Cambridgepark Drive, Cambridge, MA 02140, USA. attila.seyhan@pfizer.com
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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