Integrated functional, gene expression and genomic analysis for the identification of cancer targets.
The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
Elizabeth
E
Iorns
Christopher J
CJ
Lord
Anita
A
Grigoriadis
Sarah
S
McDonald
Kerry
K
Fenwick
Alan
A
Mackay
Charles A
CA
Mein
Rachael
R
Natrajan
Kay
K
Savage
Narinder
N
Tamber
Jorge S
JS
Reis-Filho
Nicholas C
NC
Turner
Alan
A
Ashworth
D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human