The Raf kinases, in particular B-Raf, are upstream of the pro-survival ERKs. 70 Many RTK oncogenic mutants signal via Raf-1/ERKs to induce cell cycle entry and proliferation, and to block apoptosis. of targeted therapy, and the molecular mechanisms that underlie that risk. We will review the importance of tyrosine kinase signaling pathways both for oncogenesis and for the survival of normal cardiomyocytes. To understand basic mechanisms of cardiomyopathy of TKIs, it is critical to understand two general classes of toxicity. The first is on-target toxicity wherein the tyrosine kinase target regulating cancer cell survival and/or proliferation (and therefore is a good target in cancer therapy), also serves an important role in normal cardiomyocyte survival, and thus inhibition leads to myocardial dysfunction. Off-target toxicity occurs when a TKI leads to toxicity via inhibition of a kinase Mitoxantrone Hydrochloride not intended to be a target of the drug. This type of toxicity is usually intrinsically related to two issues – 1) the inherent non-selectivity of TKIs and 2) a pattern towards multi-targeting or purposefully designing drugs to inhibit a broad range of targets that include kinases regulating both tumorigenesis and tumor angiogenesis. Although multi-targeting may broaden efficacy of an anti-cancer agent, likelihood of toxicity would also increase. With the growing number of FDA-approved brokers, and scores more in development,6, 7 some of these will inhibit novel kinase targets for which little or no clinical data exist on risk of heart failure or cardiomyopathy. Therefore, we will also review basic science studies that raise concerns over potential risk of cardiomyopathy in patients treated with drugs that inhibit these kinases. Finally, we will discuss cardiovascular considerations for development of future targeted therapy that may maximize anti-tumor effects, while minimizing cardiac effects in patients being treated with these potentially life-saving medications. Tyrosine Kinases in Signal Transduction Response to extracellular and intracellular stimuli is vital for all those complex living organisms. Activation of signal transduction cascades allows a relatively small stimulus to be amplified into a larger biologic response, such as the re-programming of gene expression.10 Tyrosine kinases, of which there are approximately 90 in the human genome,11 play central roles in transducing extracellular signals (i.e. growth factors and cytokines) into activation of signaling pathways that regulate cell growth, differentiation, metabolism, migration, and programmed cell death (apoptosis). Tyrosine kinases are families of enzymes that catalyze transfer of a phosphate residue from ATP to tyrosine residues in other proteins (substrates). Phosphorylation can change activity, subcellular location, stability, etc. of the phosphylorated substrate protein. There are two major classes of tyrosine kinases. Receptor tyrosine kinases (RTKs) Rabbit polyclonal to ACADL are embedded in the cell membrane with an Mitoxantrone Hydrochloride extracellular ligand-binding domain name and an intracellular kinase domain name that signals to the interior of the cell. In contrast, non-receptor tyrosine kinases (NRTKs) are located within the cell. By their location, tyrosine kinases can mediate transduction of both extracellular and intracellular signals. Because of their crucial role in normal cellular communication and maintenance of Mitoxantrone Hydrochloride homeostasis, tyrosine kinase activity is usually tightly regulated. 10 Tyrosine kinases are normally quiescent until activated by extracellular stimuli or ligands, such as growth factors (e.g. vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF)) or intracellular stimuli (such as oxidant stress, activating non-receptor tyrosine kinases). An exquisite balance between activity of tyrosine kinases and of tyrosine phosphatases which mediate dephosphorylation of tyrosine residues and therefore act in contra to kinases, controls the timing and duration of cell signaling. Abnormal Tyrosine Kinase Activity and Cancer: Malignant transformation and.