TP53, a well-known tumor suppressor gene, is frequently inactivated by mutation or deletion in a majority of human tumors. 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 due to the complexity of p53 signaling. Therefore, identification of vulnerabilities conferred by TP53 deletion or mutation is a major challenge to target p53 aberrancy in human cancer. We demonstrate that genomic deletion of TP53 frequently encompasses neighboring essential genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is always co-deleted with TP53 in human cancers. Hemizygous loss of TP53/POLR2A occurs in 53% of colorectal cancers (CRC), 62% of breast cancers, 75% of ovarian cancers, and 41% of pancreatic cancers. POLR2A encodes the largest and catalytic subunit of RNA polymerase II complex. It is specifically inhibited by ?-Amanitin, a cyclic 8-aa peptide toxin found in the death cap mushroom (Amanita phalloides). POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer (CRC). Suppression of POLR2A selectively inhibits proliferation, survival and tumorigenic potential of CRC cells with hemizygous TP53 loss in a p53- independent manner. Previous clinical applications of ?-Amanitin have been limited due to its liver toxicity. Free ?-Amanitin causes apoptosis and necrosis of hepatocytes by interacting with the hepatocyte-specific transporting protein OATP1B3 (10). However, ?-Amanitin is no longer substrate for OATP1B3 when coupled to antibodies. Therefore, ?-Amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with significantly reduced toxicity. Our study has shown that low doses of ?-Amanitin-conjugated anti- EpCAM (Epithelial Cell Adhesion Molecule) antibody lead to complete tumor regression in murine models of human CRC with hemizygous deletion of POLR2A. The preclinical studies in this application were recently published in Nature, which provide the foundation for future clinical trials. There is already discussion regarding the potential for initiation of a clinical trial based on our work. We propose that hemizygous deletion of TP53 in human cancers creates a therapeutic window between normal and cancer cells, and that PORL2A is a novel and druggable target in cancers with such genomic alterations.

Public Health Relevance

Hemizygous deletion of the tumor suppressor TP53 gene is a frequent genomic event in human cancers. As a gene essential for cell survival, the POLR2A gene is always co-deleted with TP53 in the cancer cell. In this proposal, we propose that hemizygous deletion of TP53 creates a therapeutic window between normal and cancer cells, and that PORL2A is a novel and druggable target in human cancers with such genomic alterations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA203737-04
Application #
9470862
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kondapaka, Sudhir B
Project Start
2017-08-09
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Genetics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Li, Yujing; Liu, Yunhua; Xu, Hanchen et al. (2018) Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nat Commun 9:4394
Liu, Yunhua; Xu, Jiangsheng; Choi, Hyun Ho et al. (2018) Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer. Nat Commun 9:4718
Liu, Yunhua; Xu, Hanchen; Van der Jeught, Kevin et al. (2018) Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer. J Clin Invest 128:2951-2965
Katreddy, Rajasekhara Reddy; Bollu, Lakshmi Reddy; Su, Fei et al. (2018) Targeted reduction of the EGFR protein, but not inhibition of its kinase activity, induces mitophagy and death of cancer cells through activation of mTORC2 and Akt. Oncogenesis 7:5
Wang, Hai; Agarwal, Pranay; Zhao, Shuting et al. (2016) Combined cancer therapy with hyaluronan-decorated fullerene-silica multifunctional nanoparticles to target cancer stem-like cells. Biomaterials 97:62-73
Han, Cecil; Yang, Lifeng; Choi, Hyun Ho et al. (2016) Amplification of USP13 drives ovarian cancer metabolism. Nat Commun 7:13525