Abstract B156: TP53 loss creates therapeutic vulnerability in colorectal cancer

Abstract

Abstract TP53, a well-known tumour suppressor gene, is frequently inactivated by mutation or deletion in a majority of 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 due to the complexity of p53 regulators and their poor drugability. Here, we demonstrate that genomic deletion of TP53 frequently encompasses neighbouring essential genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such an essential house-keeping gene that is virtually co-deleted with TP53 in many types of human cancer. It encodes the largest and catalytic subunit of RNA polymerase II complex, which is specifically inhibited by α-Amanitin. Our analysis of clinical samples and cancer cell lines in The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopaedia (CCLE) reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal tumours. Suppression of POLR2A with α-amanitin or short-hairpin RNAs, selectively inhibits 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 due to its liver toxicity. However, we found that α-amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with dramatically reduced toxicity. Here, we show that low doses of α-amanitin-conjugated anti-EpCAM (Epithelial Cell Adhesion Molecule) antibody lead to complete tumour regression in murine models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a novel therapeutic approach for cancers harbouring such common genomic alterations. Citation Format: Yunhua Liu, Xiongbin Lu. TP53 loss creates therapeutic vulnerability in colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B156.