Signalling molecules as targets in cancer therapy

Activating mutations and overexpression of several human oncogenes stimulate the enzymatic activity of mitogen-activated protein kinases (MAPKs). This family of proteins controls a broad variety of downstream effectors involved in normal and aberrant cell proliferation, survival and death. The kinase activity of some isoforms is found highly increased in several types of human tumors or it is required for the therapeutic effect of some antitumoral drugs to induce cell death. The complexity of the signal transduction pathways activated by MAPKs, the opposite effects of different isoforms on cell growth, and the multiple cross talks among them, have challenged the rational design for specific targeting of these proteins. Several inhibitors with a considerable specificity are currently used to investigate the role of distinct MAPKs in cellular and animal models and because of their effect as inhibitors of cell growth and activators of apoptosis, some of them are being used in cancer clinical trials. Still, the possibility of a successful usage of these compounds in the cure of disease will be determined by the ability to decipher the complexity of MAPKs signaling routes, to develop new inhibitory compounds with low or null secondary effects, and to identify the precise fingerprint of each tumor type and variations among cancer patients. This chapter underscores the role of different MAPKs in cancerous cell proliferation and overview the most promising small molecule inhibitors being used as antitumorals in clinical trials.