Publication Date:
2015-04-23
Description:
TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by alpha-amanitin. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with alpha-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of alpha-amanitin have been limited owing to its liver toxicity. However, we found that alpha-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity. Here we show that low doses of alpha-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417759/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417759/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yunhua -- Zhang, Xinna -- Han, Cecil -- Wan, Guohui -- Huang, Xingxu -- Ivan, Cristina -- Jiang, Dahai -- Rodriguez-Aguayo, Cristian -- Lopez-Berestein, Gabriel -- Rao, Pulivarthi H -- Maru, Dipen M -- Pahl, Andreas -- He, Xiaoming -- Sood, Anil K -- Ellis, Lee M -- Anderl, Jan -- Lu, Xiongbin -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA136549/CA/NCI NIH HHS/ -- R21 CA185742/CA/NCI NIH HHS/ -- U54 CA151668/CA/NCI NIH HHS/ -- England -- Nature. 2015 Apr 30;520(7549):697-701. doi: 10.1038/nature14418. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Gynaecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. ; 1] Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Paediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Heidelberg Pharma GmbH, Ladenburg 68526, Germany. ; Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA. ; 1] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Gynaecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901683" target="_blank"〉PubMed〈/a〉
Keywords:
Alpha-Amanitin/adverse effects/chemistry/pharmacology/therapeutic use
;
Animals
;
Antibodies/chemistry/immunology
;
Antigens, Neoplasm/immunology
;
Catalytic Domain
;
Cell Adhesion Molecules/immunology
;
Cell Line, Tumor
;
Cell Proliferation/drug effects
;
Colorectal Neoplasms/*drug therapy/enzymology/*genetics/pathology
;
Databases, Genetic
;
Disease Models, Animal
;
Female
;
Gene Deletion
;
Gene Dosage/genetics
;
Genes, p53/*genetics
;
Humans
;
Immunoconjugates/adverse effects/chemistry/immunology/therapeutic use
;
Mice
;
Protein Subunits/chemistry/deficiency/genetics
;
RNA Polymerase II/antagonists & inhibitors/chemistry/deficiency/genetics
;
Tumor Suppressor Protein p53/biosynthesis/*deficiency/genetics
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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