NDLI: A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments

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A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments

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Molecular BioSystems Vol - 7 Issue - 5

Molecular BioSystems Vol - 7 Issue - 4

Molecular BioSystems Vol - 7 Issue - 3

Molecular BioSystems Vol - 7 Issue - 2

Molecular BioSystems Vol -6

Molecular BioSystems Vol -5

Molecular BioSystems Vol -4

Molecular BioSystems Vol -3

Molecular BioSystems Vol -2

A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments

Content Provider	Royal Society of Chemistry (RSC)
Author	Liu, Yan Seyhan, Attila A. Liu, Wei Choe, Sung Ryan, Terence E. McGraw, John Woods, Matthew Murray, Stuart Varadarajan, Usha Eckert, Amy
Copyright Year	2011
Abstract	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.
Starting Page	1974
Ending Page	1989
Page Count	16
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	7
Issue Number	6
Journal	Molecular BioSystems
DOI	10.1039/c0mb00294a
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Tyrosine Ubiquitin Estrogen receptor RNA interference Neu! Enzyme inhibitor Tumor hypoxia Breast cancer EGFR Epidermal growth factor receptor Tyrosine kinase Cytarabine Paclitaxel Gene regulatory network Clinical trial Apoptosis Cyclic adenosine monophosphate
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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