TP53 loss creates therapeutic vulnerability in colorectal cancer
Authors: Cristian Rodriguez-Aguayo
Cecil Han
Yunhua Liu
Dahai Jiang
Cristina Ivan
Xiongbin Lu
Gabriel Lopez-Berestein
Dipen M Maru
Guohui Wan
Anil K Sood
Xinna Zhang
Lee M Ellis
Pulivarthi H Rao
Xiaoming He
Xingxu Huang
Jan Anderl
Andreas Pahl
Journal: Nature (2015)
Discipline: Multidisciplinary
Keywords: TP53; tumour suppressor gene; p53; mutation; deletion
Affiliations: 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.

Abstract:  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 α-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 α-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 α-amanitin have been limited owing to its liver toxicity. However, we found that α-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity. Here we show that low doses of α-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. 

Retracted: No

PubPeer comments:
 Extended Data Figure 9 appears to include some images which overlap, after rotation. *** ![file] , 
 Dear colleagues at PubPeer, Thank you for bringing to our attention duplicated figures. We apologize for this unintended and inadvertent error. After receiving the comment, we immediately approached Dr. Yunhua Liu, the first author of this 2015 Nature paper. With thorough examination of our original data, we found out that indeed the representative images of caspase-3 in the POLR2A-loss group were inadvertently taken from a pool of images in the POLR2A-neutral group. In our pathological analysis of the tissue samples from the in vivo experiments, there were a large number of raw images that were analyzed after cropping and quantified. The caspase-3 images from the POLR2A-neutral group were repeatedly used by mistake in the POLR2A-loss group. While this mistake does not affect the conclusion of this report, we deeply apologize for this careless mistake as it should have been identified before submission. To avoid this type of mistakes, our team will use a new standard operating procedure by including an independent review of all figures to avoid accidental and unintentional duplications. Finally, we appreciate your efforts in post-publication reviews. Below is our corrected figure: ![file] , 
 #2 Thank you for your prompt response and kind words. You may also wish to review the other papers at [this link] . , 
 It appears that there may be a [patent] held by two of the authors related to subjects discussed in this paper. Could the authors comment on whether that patent was applied for prior to acceptance of this paper? , 
 Another reader (LS) shared the dates on the patent and paper: *** ![file] *** ![file] , 
 https: forbetterscience.com 2021 04 19 xiongbin-lu-nanobombs-cancer-with-fluorescent-nude-mouse-recycling Indiana University Research Integrity Officer Shelley Bizila u201cMy office, IUu2019s Research Integrity Office, is responsible for receiving any allegations of possible falsification, fabrication or plagiarism and for administering IUu2019s policy. As such, our office has previously been made aware of the concerns you cite and has already started an inquiry process. We will proceed according to our policy to ensure any concerns of possible research misconduct are addressed. u201c , 
 Published: 25 August 2021  In Extended Data Fig. 9a of this Article, the casp-3 immunohistochemical staining images in the HEA125 and Ama-3 treatment groups of POLR2Aloss tumours were inadvertently taken from serial tissue sections of a tumour in the Ama-3 treatment group of POLR2Aneutral tumours. In Fig. 1 of this Amendment, we have replaced these two images with corrected ones (highlighted by red boxes). All of the original casp-3 staining images from the POLR2Aneutral and POLR2Aloss tumours with indicated treatments are shown in Supplementary Information to this Amendment. The immunohistochemistry staining images were not used for quantitative analysis in the study, and this mistake does not affect the conclusions of the original Article. The original Article has not been corrected online. ![file] *** The affected panels are highlighted by red boxes. ,