Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics.
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.
Chan
Denise A
DA
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5152, USA.
Giaccia
Amato J
AJ
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D005804:Genes, Lethal / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
D011725:Pyridines; C530878:STF 62247; D013844:Thiazoles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret