spliceostatin A, which inhibits the SF3b subunit of the U2 snRNP, thereby modulating the AS of genes important for cell cycle control. LOXO 101 manufacturer Considering the important control exerted by protein kinases on AS, modulation of their activity represents a potential approach for the development of new drugs targeting RNA splicing in cancer therapy. These suggestions are supported by recent reports highlighting the high efficacy of SRPK1/2 inhibitors in reducing angiogenesis through the negative modulation of the AS of the proangiogenic splice variant VEGFxxx gene. Considering the great impact that SRPKs have on the splicing activity of SR proteins and the large number of AS events that they regulate, modulation of SRPK activity could be a powerful tool in the emerging field of splicing-modulating therapies. It is also important to mention that SRSF1, a well-known target of SRPKs, is upregulated in human cancers and functions as an oncogene. For the same reasons, CLKs are a fascinating chemotherapeutic target too, and important efforts are being made for the realization of selective and efficient CLKs inhibitors. Signal-transduction pathways able to modulate the phosphorylation status of SR proteins or the activity of other RBPs represent another potential druggable target for RNA splicing modulation. For example, it has been recently shown that amiloride, a well-known diuretic, can reduce proliferative and invasive properties of both hepatocellular carcinoma and leukemia cancer cells by inducing PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19819247 hypophosphorylation of SR-proteins. Genome-wide exon array analysis has demonstrated that amiloride treatment induces the modulation of a large number of AS events, and, in particular, it negatively regulates protumoral splice variants of several genes, such as the antiapoptotic – or proinvasive RON. Reduced phosphorylation levels of AKT and ERKs were observed after amiloride treatment, suggesting that this drug reduces SR protein phosphorylation through inactivation of these kinases. Deregulation of signal-transduction pathways in cancer cells is a general feature, and much effort has been made in order to develop chemotherapeutic agents that efficiently International Journal of Cell Biology inhibit the activity of the kinases mediating the intracellular transduction of these signals, such as AKT or kinases of the MAPK and SRC families. As many of these inhibitors are already in clinical practice, and many of them are undergoing promising clinical trials, it would be very interesting to understand whether their antiproliferative and cytotoxic effects could be partly due to their ability to interfere with AS events regulated by these kinases. Even more attractive is the possibility to exploit protein kinase inhibitors to selectively affect splicing decisions in order to restore in cancer cells 
a normal, nonpathological AS pattern. The work in the laboratory of C. Sette was supported by Association for International Cancer Research, the Associazione Italiana Ricerca sul Cancro, and Istituto Superiore della Sanit`. In the past several decades cancer research has focused on genetic alterations such as mutations, copy number variations, and translocations that are detected in malignant tissues and contribute to the initiation and progression of cancer. In recent years it is becoming clear that epigenetic changes, including transcriptional and posttranscriptional alterations, also play a major role in cancer development and thus should be the direction of futu
