TP53 loss creates therapeutic vulnerability incolorectal cancer.

Abstract

TP53 , a well-known tumour suppressor gene, is frequently inactivated by mutation or deletion in a majority of human tumours1,2. A tremendous effort has been made to restore p53 activity in cancer therapies3–7. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of p53 signalling. 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 a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of RNA polymerase II complex, which is specifically inhibited by α-Amanitin8,9. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopaedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer (CRC). Suppression of POLR2A with α-Amanitin or small interfering RNAs, selectively inhibits proliferation, survival and tumorigenic potential of CRC cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-Amanitin have been limited due to its liver toxicity10. However, we found that α-Amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with reduced toxicity11. 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 CRC with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a novel therapeutic approach for human cancers harbouring such common genomic alterations.