Regulation of c-Raf-1: therapeutic implications.
The mitogen activated protein kinase (MAPK) or Ras/Raf/MAPK kinase (MEK)/ERK signaling cascade is a ubiquitously expressed intracellular signaling pathway that transmits mitogenic stimuli to the nucleus through a series of sequential phosphorylation events and controls such cellular functions as proliferation, differentiation, and apoptosis. Components of this pathway such as ras and raf are oncogenes and as such aberrancy in their encoded proteins results in malignant transformation. The MAPK pathway is dysregulated in approximately 30% of all human tumors and therefore targeting specific components of this pathway that regulate pleiotropic cellular processes using such strategies as isoprenylation inhibitors, antisense oligodeoxyribonucleotides, and inhibitors of the kinase function represent attractive therapeutic options. raf kinase, a downstream effector of ras, has been known to be functionally aberrant in various human tumors. The 3 isoforms of raf have been studied extensively, and agents targeting c-raf are presently undergoing early-phase clinical testing. The outcomes of these trials have wide-ranging clinical implications in the management of cancers. This review addresses the rationale for targeting raf, the diverse cellular functions regulated by c-raf, and the current status of various pharmacological approaches targeting c-raf.
Beeram
Muralidhar
M
Division of Medical Oncology-Hematology, Institute for Drug Development, University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, Zeller Building Z 414-B, San Antonio, TX 78229, USA. mbeeram@idd.org
Patnaik
Amita
A
Rowinsky
Erick K
EK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D013873:Thionucleotides / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D020319:Oligodeoxyribonucleotides, Antisense; D010671:Phenylurea Compounds; D011725:Pyridines; D013873:Thionucleotides; D009536:Niacinamide; C099587:ISIS 5132; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf