Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).

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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.

Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1−/− mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1−/− mice, IRF-2−/− mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1−/− and IRF-2−/− mice, but the underlying mechanism differs. NK (but not NK+ T) cell numbers are decreased in IRF-2−/− mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.

Blockade of prostaglandin (PG) production by COX inhibitors is the treatment of choice for inflammatory pain but is also prone to severe side effects. Identification of signaling elements downstream of COX inhibition, particularly of PG receptor subtypes responsible for pain sensitization (hyperalgesia), provides a strategy for better-tolerated analgesics. Here, we have identified PGE2 receptors of the EP2 receptor subtype as key signaling elements in spinal inflammatory hyperalgesia. Mice deficient in EP2 receptors (EP2-/- mice) completely lack spinal PGE2-evoked hyperalgesia. After a peripheral inflammatory stimulus, EP2-/- mice exhibit only short-lasting peripheral hyperalgesia but lack a second sustained hyperalgesic phase of spinal origin. Electrophysiological recordings identify diminished synaptic inhibition of excitatory dorsal horn neurons as the dominant source of EP2 receptor-dependent hyperalgesia. Our results thus demonstrate that inflammatory hyperalgesia can be treated by targeting of a single PG receptor subtype and provide a rational basis for new analgesic strategies going beyond COX inhibition.