TP53 loss creates therapeutic vulnerability in colorectal 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.

RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif

“…Inhibition of a ubiquitous and essential pathway in cancer could overcome, in part, the drug resistance conferred through the genetic heterogeneity of the disease. Indeed, a recent study has shown that many cancers have a concomitant hemizygous loss of POLR2A (RPB1) and p53, rendering them more vulnerable to transcription inhibition (49). Development of small molecules that selectively obstruct the pol II transcription machinery in a sequence-specific manner would present a therapeutic strategy to target transcription addiction in cancer cells.…”

“…Given the potent sequence-specific inhibition by polyamide interference, and the demonstrated antitumor activity in xenografts with low host toxicity, it would be very attractive to consider whether there is a role in cancer therapy for these molecules. Transcription inhibition has been explored as a therapeutic strategy in cancer treatment (46)(47)(48)(49). Inhibition of a ubiquitous and essential pathway in cancer could overcome, in part, the drug resistance conferred through the genetic heterogeneity of the disease.…”

Tumor-Suppressor Functions of the TP53 Pathway

“…The large chromosomal deletion results in the loss of several additional genes and this raises the possibility that cooperating lesions on 17p may contribute to human cancers. For example, a gene encoding a component of the RNA polymerase II complex, POLR2A, is almost always codeleted in human cancers with the TP53 gene, and this has functional impact on the resulting tumor (Liu et al 2015). These are important features of human cancer that are inextricable from the question of understanding how loss or mutation of TP53 leads to the development of cancer.…”

Ovarian cancer

“…However, TP53 gene therapy using adenoviral vectors has been met with limited success partly due to toxicity related to the approaches used (157,158). Other emerging therapies targeting tumors carrying mutant TP53 include COTI-2, which is thought to induce a 'wild-typelike' conformational change in mutant p53 and is currently in clinical trials (159). LGSC is investigating trametinib (GSK 1120212) in patients with recurrent or progressive LGSC (212), but this study has been suspended due to problems with the drug supply.…”