title: TP53 loss creates therapeutic vulnerability in colorectal cancer.
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.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Cecil
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Wan
authors.affiliation: School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: 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.
authors.forename: Dahai
authors.initials: D
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Paediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
authors.affiliation: Heidelberg Pharma GmbH, Ladenburg 68526, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pahl
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.affiliation: Heidelberg Pharma GmbH, Ladenburg 68526, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Anderl
authors.affiliation: 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.
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
mesh_terms: D053959:Alpha-Amanitin / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D020134:Catalytic Domain; D015815:Cell Adhesion Molecules / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D030541:Databases, Genetic; D004195:Disease Models, Animal; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D021122:Protein Subunits / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D053959:Alpha-Amanitin; D000906:Antibodies; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D018796:Immunoconjugates; D021122:Protein Subunits; D016159:Tumor Suppressor Protein p53; D012319:RNA Polymerase II