Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics

Cell Cycle. 2008 Oct;7(19):2987-90. doi: 10.4161/cc.7.19.6776. Epub 2008 Oct 12.

Abstract

Standard cytotoxic agents for treating cancer were developed based on their effectiveness to kill rapidly dividing cells, not on their ability to selectively kill cancer cells and spare normal tissue. Much of contemporary cancer research is aimed at identifying specific molecular features of cancers to directly target tumor cells with the hope of reducing or eliminating unwanted side effects. Targeted therapy for the treatment of cancer can be divided into two main categories: monoclonal antibodies and small molecules. In this Perspective, we review the approach of synthetic lethality to target cancer, specifically renal cell carcinoma. The concept of synthetic lethality is used to describe a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death. Recently, we identified a compound, STF-62247, that functions in a synthetic lethal manner to the loss of VHL, a mutation found in the majority of renal cell carcinomas.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Genes, Lethal / genetics*
  • Humans
  • Models, Biological
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors
  • Proto-Oncogene Proteins c-ret / metabolism
  • Pyridines / pharmacology
  • Thiazoles / pharmacology
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Pyridines
  • STF 62247
  • Thiazoles
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Proto-Oncogene Proteins c-ret