Editorial [Hot Topic: Novel Kinase Inhibitors in Cancer Therapy (Guest Editors: Ezra E.W. Cohen and Nikolai G. Rainov)]

Tyrosine kinases (TK) were first described by Hunter and Cooper in the late 1970s as tyrosine-specific protein kinases encoded by transforming viruses and their normal cellular homologues [1]. Just a few years later it became already known that a number of oncogenes represented TKs [2]. It is now well known that TK are important mediators of the intracellular signaling cascade and play a key role in diverse biological processes such as growth, differentiation, metabolism, and apoptosis in response to external and internal stimuli. Although TK activity is tightly regulated in normal cells, they may acquire transforming functions due to mutations, overexpression, and autocrine or paracrine stimulation, thus leading to development and maintenance of malignancy [3]. The oncogenic activation of TK in cancer cells can be blocked by inhibitors with different molecular structure and specificity. Such inhibitors have been actively developed and tested particularly in the last decade as a promising approach to innovative genome-based cancer therapeutics [4]. The current hot topics issue of RRCT focuses on the biological role TK play in different human malignancies, as well as on different approaches for TK inhibition, such as small molecule inhibitors, monoclonal antibodies, heat shock proteins, and others. Small molecule inhibitors of TK (SMI-TK) are particularly exciting agents and have attracted much attention in the articles in this issue and in the biomedical community in general. Most SMI-TK compete with the ATP binding site of the catalytic domain of several oncogenic TK. They are usually orally bioavailable with a favorable safety profile that can be combined with standard chemotherapy or radiation therapy. Several SMI-TK have been found to have significant antitumor activity and have been approved for clinical use in some tumor entities or are currently in advanced clinical trials for others. Such drugs are imatinib mesylate, gefitinib, erlotinib, lapatinib, canertinib, semaxinib, vatalanib, sorafenib, sunitinib, and leflunomide. SMI-TK are thus an important and large new class of targeted drugs that interfere with specific cell signaling pathways and allow relative target-specific therapy for TK-driven malignancies. The pharmacological properties and anticancer activities of the most important of these inhibitors are discussed in the present issue, mostly in the context of the particular tumor entities. The use of TK-targeted therapies is naturally not without limitations. Such are the development of resistance or the lack of tumor response in some types of malignancies. The availability of new generations of molecularly designed SMI-TK and improved patient selection may help overcome some of these problems in the future. The application of modern proteomic techniques and increasing knowledge of the human kinome will aid in speeding up the TK drug discovery process and will allow faster introduction of experimental TK inhibitors to clinical applications. In the first review article in this issue, Drs. Ren, Yang, and Rainov present the application of TK inhibitors to a specific disease, malignant glioma. With few effective therapeutic options for patients with glioma, this has been an area of active study with respect to novel agents. In fact, the biology of the disease would suggest that targeting specific proteins, such as EGFR, PDGFR, VEGFR, the Ras/Raf/MAPkinase pathway and the PI3K/Akt/mTOR pathway would be efficacious. It is however evident that the development of these agents in glioma is in its early stages. Some agents have begun to show activity in select patient groups although the molecular heterogeneity of the disease may ultimately limit the universal application of any single agent. In the second review article, Dr. Smith reviews the mammalian target of rapamycin (mTOR) and highlights its role in the genesis of malignant Non-Hodgkin lymphoma (NHL). MTOR is a central transducer of growth signals in normal and neoplastic cells via translational modulation. Under normal conditions, mTOR utilizes various companion proteins and upstream signals from PI3K/Akt to sense favorable environments for growth and cell cycle progression. Rapamycin is the prototype of all mTOR inhibitors, and works by binding to the 5’ end of the mTOR protein containing the FKBP12-rapamycin-binding domain component. Three mTOR inhibitors (MTI) have progressed through phase I and II clinical trials..........