SRC family kinases: potential targets for the treatment of human cancer and leukemia.
The inherited or acquired deregulation of protein kinase activity has been implicated in the pathogenesis of many human diseases, including cancer. Therefore, the inhibition of kinases has been proposed to be a promising strategy in the context of anti-cancer treatment. Many other kinases have been selected as drug discovery targets based on the prevalence of mutations, over-expression and unscheduled activation in human cancer. Of the various protein kinases chosen, Src family kinases are amongst the most extensively studied kinase oncogenes in academia and industry. This review focuses on our current understanding of the deregulation and role of Src family kinases in human cancer and leukemia. Recent data implicate the action of c-Src in cancer metastasis, mediated by up-regulation of various protease systems (calpain, uPA) as well as disruption of E-cadherin signalling. Moreover, novel roles of various Src family members in the development of human leukemia have been found. New insights into downstream signalling mechanisms, including the activation of STAT3, PDK1 and Akt, further corroborate the importance of Src family kinases in tumorigenesis and chemoresistance. Despite our rather clear understanding of Src family kinases as pro-oncogenes no Src family kinase inhibitor has entered a clinical trial so far. This review will discuss prerequisites to be fulfilled for clinically targeting c-Src and its homologues using small molecule drugs.
Warmuth
Markus
M
GNF - Genomics Institute of the Novartis Research Foundation, Biological Chemistry, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. mwarmuth@gnf.org
Damoiseaux
Robert
R
Liu
Yi
Y
Fabbro
Doriano
D
Gray
Nathanael
N
D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000503:physiopathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use
D019061:src-Family Kinases