Dasatinib in solid tumors.

IMPORTANCE OF THE FIELD: Dasatinib is an oral, potent adenosine triphosphate-competitive inhibitor of multiple tyrosine kinases including BCR-ABL, c-KIT, platelet-derived growth factor receptor, and Src family kinases (SFKs). It has gained much attention for its use in chronic myeloid leukemia and for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. However, dasatinib is also being explored in solid tumors in ongoing Phase I and II clinical trials. AREAS COVERED IN THIS REVIEW: The clinical efficacy of dasatinib in a wide variety of solid tumors and important Phase I/II studies utilizing dasatinib and the optimal dosage used in solid tumors. A literature search was conducted using PubMed/MEDLINE, www.clinicaltrials.gov , and the American Society of Clinical Oncology websites to find relevant Phase I/II clinical trials during 1987-2009. WHAT THE READER WILL GAIN: The understanding that the biology and mechanism of Src activation in tumors are not well understood and finding the optimal use of SFK inhibitors in the clinical setting requires further investigation. TAKE HOME MESSAGE: In reviewing the clinical safety data of dasatinib in its current use as a Src inhibitor in a wide variety of solid malignancies, dasatinib appears to be safe and is a promising agent for the treatment of metastatic solid tumors refractory to standard therapies.

Src kinases as therapeutic targets for cancer.

Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.