Double-edged sword of the new cancer therapeutics.

P rotein kinases regulate a vast array of cellular processes including, but not limited to, cell proliferation, differentiation , motility, death, and survival. They regulate these and other processes by attaching phosphate groups onto various proteins (substrates), changing the substrate's activity, sub-cellular localization, and resistance to (or promotion of) cell death. There are Ͼ500 kinases in the human genome (referred to as the kinome). Dysregulation of kinases is responsible for a multitude of pathologies, and nowhere is that more evident than in cancer. 1 Numerous malignancies are driven by mutations in protein kinases. The first definitive identification of a mutation within a kinase leading to a malignancy was chronic myeloid leukemia, driven by the balanced translocation that creates the Philadelphia chromosome. 2 The resulting fusion protein of BCR (for breakpoint cluster region, a protein kinase of poorly understood function) and Abl, a tyrosine kinase implicated in a number of cellular processes, leads to consti-tutive activation of the fusion protein and transformation of myeloid progenitors in the bone marrow, driving the malig-nancy. Since that initial discovery, numerous mutations in kinases have been identified that drive a wide variety of malignancies, either directly promoting cancer growth or promoting neovascularization of the tumor. 3 In the case of chronic myeloid leukemia, 3 kinase inhibitors have been approved for use (imatinib, dasatinib, and nilotinib, with others in development), and they have literally revolutionized the treatment of the disease, leading to prolonged remissions in the majority of patients. 4 The identification of these drugs that target BCR-Abl and other drugs that target a very wide range of other mutated or overexpressed kinases driving other cancers has become the primary focus of drug development for many pharmaceutical companies. Further fostering development is the relative ease of getting these drugs to market compared, for example, to novel drugs for treating heart failure. 5 Although many of these agents have significantly improved outcomes in patients, in some instances it has come at a cost of a variety of toxicities, including cardiovascular toxicity. 6,7 This was something of a surprise because it was hoped that these targeted therapeutics, which were believed to specifically inhibit the culprit kinase, would have minimal toxicity, especially when compared to standard chemothera-peutics such as the anthracyclines. In many instances, that has proven to be the case, with notable exceptions (see below). In this issue of Circulation, Montani et al 8 identify a new kinase …