Src Family Kinase Inhibitors in Cancer Therapy pp.125-152
Authors: (Faye M. Johnson, Gary E. Gallick - Dept. of Thoracic/Head and Neck Medical Oncology, The Univ. of Texas, Houston, TX, and others)
Abstract: The first cellular oncoprotein to be studied was the viral protein v-src, a tyrosine kinase. Protein tyrosine kinases were found later to be key regulators of cellular signaling pathways that control important processes in cancer progression, including transformation, proliferation, survival, invasion, and angiogenesis. Protein tyrosine kinase inhibitors are a relatively new class of agents that have been developed to exploit the importance of tyrosine kinases in cancer biology. One potential therapeutic target for which agents have been developed recently is the src family of kinases (SFKs). SFKs are nonreceptor tyrosine kinases involved in signal transduction in a wide variety of malignancies. Interest in SFKs has increased because of the development of pharmacologic SFK inhibitors that have exhibited initial clinical success and low toxicity. c-Src is the best-studied member of the Src family and the one most often involved in cancer progression. c-Src has multiple substrates, and its inhibition can lead to changes in proliferation, motility, invasion, survival, and angiogenesis. SFKs have been demonstrated to be important for the progression of many epithelial tumors, such as cancers of the colon, pancreas, breast, lung, head and neck, and prostate. SFKs also are expressed in sarcomas, melanoma, and hematologic malignancies. Several inhibitors of the SFKs are in clinical development. Four SFK inhibitors are currently being studied in clinical trials and have been well tolerated; data on their antitumor effects are pending. Future clinical development of these inhibitors will include completion of trials in patients with solid tumors, definition of sensitive populations, and trials of combination therapy.