title: A genome-wide RNAi screen identifies novel targets of neratinib resistance leading to identification of potential drug resistant genetic markers.
abstract: Neratinib (HKI-272) is a small molecule tyrosine kinase inhibitor of the ErbB receptor family currently in Phase III clinical trials. Despite its efficacy, the mechanism of potential cellular resistance to neratinib and genes involved with it remains unknown. We have used a pool-based lentiviral genome-wide functional RNAi screen combined with a lethal dose of neratinib to discover chemoresistant interactions with neratinib. Our screen has identified a collection of genes whose inhibition by RNAi led to neratinib resistance including genes involved in oncogenesis (e.g. RAB33A, RAB6A and BCL2L14), transcription factors (e.g. FOXP4, TFEC, ZNF), cellular ion transport (e.g. CLIC3, TRAPPC2P1, P2RX2), protein ubiquitination (e.g. UBL5), cell cycle (e.g. CCNF), and genes known to interact with breast cancer-associated genes (e.g. CCNF, FOXP4, TFEC, several ZNF factors, GNA13, IGFBP1, PMEPA1, SOX5, RAB33A, RAB6A, FXR1, DDO, TFEC, OLFM2). The identification of novel mediators of cellular resistance to neratinib could lead to the identification of new or neoadjuvant drug targets. Their use as patient or treatment selection biomarkers could make the application of anti-ErbB therapeutics more clinically effective.
authors.affiliation: Systems Biology, Global Biotherapeutics, Pfizer Inc., 200 Cambridgepark Drive, Cambridge, MA 02140, USA. attila.seyhan@pfizer.com
authors.forename: Attila A
authors.initials: AA
authors.lastname: Seyhan
authors.forename: Usha
authors.initials: U
authors.lastname: Varadarajan
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Terence E
authors.initials: TE
authors.lastname: Ryan
mesh_terms: D045744:Cell Line, Tumor; D004194:Disease / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D005819:Genetic Markers; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D005819:Genetic Markers; D011804:Quinolines; D034741:RNA, Small Interfering; C487932:neratinib