TP53 loss creates therapeutic vulnerability in colorectal cancer
Liu, Yunhua1; Zhang, Xinna2,3; Han, Cecil1; Wan, Guohui1; Huang, Xingxu4; Ivan, Cristina2,3; Jiang, Dahai2,3; Rodriguez-Aguayo, Cristian3,5; Lopez-Berestein, Gabriel3,5; Rao, Pulivarthi H.6; Maru, Dipen M.7; Pahl, Andreas8; He, Xiaoming9; Sood, Anil K.1,2,3; Ellis, Lee M.10; Anderl, Jan8; Lu, Xiongbin1,3
Source PublicationNATURE
AbstractTP53, 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 a-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 a-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.
Indexed BySCI
Funding ProjectNIH[U54 CA151668]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000353689700054
Original Document TypeArticle
Citation statistics
Cited Times:132[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Corresponding AuthorLu, Xiongbin
Affiliation1.Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
2.Univ Texas MD Anderson Canc Ctr, Dept Gynaecol Oncol & Reprod Med, Houston, TX 77030 USA
3.Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA
6.Baylor Coll Med, Dept Paediat, Houston, TX 77030 USA
7.Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
8.Heidelberg Pharma GmbH, D-68526 Ladenburg, Germany
9.Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA
10.Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA
Recommended Citation
GB/T 7714
Liu, Yunhua,Zhang, Xinna,Han, Cecil,et al. TP53 loss creates therapeutic vulnerability in colorectal cancer[J]. NATURE,2015,520(7549):697-U286.
APA Liu, Yunhua.,Zhang, Xinna.,Han, Cecil.,Wan, Guohui.,Huang, Xingxu.,...&Lu, Xiongbin.(2015).TP53 loss creates therapeutic vulnerability in colorectal cancer.NATURE,520(7549),697-U286.
MLA Liu, Yunhua,et al."TP53 loss creates therapeutic vulnerability in colorectal cancer".NATURE 520.7549(2015):697-U286.
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