TP53 loss creates therapeutic vulnerability in colorectal cancer

Genomic deletion of the tumour suppressor TP53 frequently includes other neighbouring genes, such as the POLR2A housekeeping gene that encodes a crucial RNA polymerase II subunit; suppression of POLR2A with α-amanitin or by RNA interference selectively inhibits the tumorigenic potential of cancer cells, and in mouse models of cancer, tumours can be selectively targeted with α-amanitin coupled to antibodies, suggesting new therapeutic approaches for human cancers. The tumour suppressor gene TP53 is inactivated by mutation or deletion in a majority of human tumours. So far, attempts to restore the activity of its product, p53, have had little success owing to the complexity of p53 signalling. This paper suggests a new approach to targeting TP53 indirectly. Genomic deletion of TP53 frequently includes other neighbouring genes, such as the POLR2A housekeeping gene that encodes a crucial RNA polymerase II subunit. Xionbin Lu and colleagues show that loss of one copy of POLR2A renders cancer cells highly sensitive to inhibitors of RNA polymerase II, such as α-amanitin. In mouse models of cancer, tumours containing the POLR2A/TP53 co-deletion can be selectively targeted with α-amanitin conjugated to antibodies that target the cancer cells. Exploiting similar selective vulnerabilies for other genomic deletions that affect essential housekeeping in addition to tumour suppressor genes may pave a way towards selective therapies for a broad range of cancers. TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours1,2. A tremendous effort has been made to restore p53 activity in cancer therapies3,4,5,6,7. 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-amanitin8,9. 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 toxicity10. However, we found that α-amanitin-based antibody–drug conjugates are highly effective therapeutic agents with reduced toxicity11. 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.