Emerging Raf inhibitors.
BACKGROUND
The Raf/MAPK kinase/extracellular-signal-regulated kinase pathway is often activated by genetic alterations in upstream signaling molecules. An integral component of this pathway, BRAF, is also activated by mutation, especially in melanoma and thyroid cancers. The Raf/MAPK kinase/extracellular-signal-regulated kinase pathway has profound effects on proliferative, apoptotic and differentiation pathways as well as the sensitivity and resistance to chemotherapeutic drugs.


OBJECTIVE
This review discusses targeting of Raf which could control abnormal proliferation in cancer and other proliferative diseases. The important roles that genetics plays in the response of patients to Raf inhibitors is also evaluated. We also discuss the rationales for approaches combining Raf inhibitors and chemotherapeutic drugs.


CONCLUSIONS
Various Raf inhibitors have been developed and are being clinically used to treat patients with melanoma, thyroid, hepatocellular and renal cell cancers. Some 'Raf-kinase inhibitors' affect other kinases which are also expressed on malignant cells; yet, these inhibitors have proven useful in the therapy of certain cancer patients. Other more recently developed Raf specific inhibitors have shown success in the treatment of tumors bearing Raf mutations. The development of Raf inhibitors has significantly advanced cancer therapy in the past decade.
McCubrey
James A
JA
Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA. mccubreyj@ecu.edu
Steelman
Linda S
LS
Abrams
Steven L
SL
Chappell
William H
WH
Russo
Suzanne
S
Ove
Roger
R
Milella
Michele
M
Tafuri
Agostino
A
Lunghi
Paolo
P
Bonati
Antonio
A
Stivala
Franca
F
Nicoletti
Ferdinando
F
Libra
Massimo
M
Martelli
Alberto M
AM
Montalto
Giuseppe
G
Cervello
Melchiorre
M
D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases