Ras family signaling: therapeutic targeting

Cancer Biol Ther. Nov-Dec 2002;1(6):599-606. doi: 10.4161/cbt.306.

Abstract

Mutationally activated and oncogenic versions of the ras genes were first identified in human tumors in 1982. This discovery prompted great interest in the development of anti-Ras strategies as novel, target-based approaches for cancer treatment. The three human ras genes represent the most frequently mutated oncogenes in human cancers. Consequently, a considerable research effort has been made to define the function of Ras in normal and neoplastic cells and to target Ras for cancer treatment. Among the anti-Ras strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (farnesyltransferase inhibitors), (2) downstream signaling (Raf and MEK protein kinase inhibitors), (3) autocrine growth factor signaling (EGF receptor inhibitors), or (4) gene expression (H-ras and c-raf-1). Although a number of these inhibitors have demonstrated potent anti-tumor activities in preclinical models, phase l-lll clinical trials have revealed unexpected complexities in Ras function and in the clinical development of target-based therapies. We review the current status of anti-Ras drug development, issues that have complicated their progression to the clinic, and possible future strategies for targeting Ras.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Clinical Trials as Topic
  • Enzyme Inhibitors / pharmacology
  • Farnesyltranstransferase
  • Forecasting
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MAP Kinase Signaling System / physiology
  • Neoplasms / drug therapy
  • Oligonucleotides, Antisense / pharmacology
  • Signal Transduction / drug effects*
  • ras Proteins / physiology*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Oligonucleotides, Antisense
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • ras Proteins