New mechanisms of signal transduction inhibitor action: receptor tyrosine kinase down-regulation and blockade of signal transactivation.
The explosion of signal transduction research over the last 10 years has provided a unique insight into the complexity of these intricate pathways. Whereas intermediates of multiple signaling pathways have been identified, understanding their function and, in particular, the interactions between them has become a daunting task. The increasing evidence that many of these pathways can cross-talk with each other via signal transactivation inevitably raises the question of how cells determine specificity in signaling. Despite the mind-numbing complexity of these pathways, progress has been made in developing highly specific and potent signal transduction inhibitors (STIs). STIs show promise in the treatment of cancer in preclinical studies and are currently in a number of clinical trials. Whereas many of these agents were "rationally designed," we barely understand their mechanisms of action. This review will highlight how recent studies using these STIs have elucidated novel mechanisms of STI action that may be used in the development of new therapeutic strategies for the treatment of cancer.
Lee
Adrian V
AV
Department of Medicine, Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA. avlee@breastcancer.tmc.edu
Schiff
Rachel
R
Cui
Xiaojiang
X
Sachdev
Deepali
D
Yee
Douglas
D
Gilmore
Andrew P
AP
Streuli
Charles H
CH
Oesterreich
Steffi
S
Hadsell
Darryl L
DL
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020239:Receptor Cross-Talk / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020794:Receptor Protein-Tyrosine Kinases