Are critical normal gene products in cancer cells the real therapeutic targets?
The majority of targets for rational anti-cancer drug development available at present have been defined by studies of early carcinogenesis. In this situation, mutations resulting in altered expression or structure of gene products, in the context of a relatively normal diploid background, provide the cell with a growth advantage. In contrast to cells studied in early carcinogenesis, however, profound chromosomal abnormalities and widespread disruption of gene expression can be found in the cells of typical cancers seen in the clinic. In addition tumour heterogeneity and genetic instability, in clinical cancers, can result in variable and elusive drug targets. The severe degree of genetic damage, seen in the clinical situation, would be expected to sufficiently disrupt the function of cell-signalling pathways, such that the highly complex and co-ordinated process of cell division, which occurs in normal cells, could no longer be effectively accomplished in the clinical cancer cell. It may therefore be relevant to consider whether certain Critical Normal Genes must be retained throughout the life of the progressively evolving cancer cell in order to enable it to continue to divide successfully. The regulatory roles of the products of such Critical Normal Genes would be expected to become particularly important in the chaotic molecular environment, which finally occurs in the typical clinical cancer cell. Here remaining Critical Normal Gene Products may be required to perform novel functions to maintain cellular integrity. Because the function of such gene products would be essential for continued cancer cell proliferation, they would not be expected to be subject to tumour heterogeneity or genetic instability as loss of function of a gene product essential to cell proliferation would inevitably result in the death of that cell. Perhaps such remaining Critical Normal Gene Products, with adapted functions critical to continued cancer cell proliferation, whose disruption may only have minimal effects within the multiple signalling pathways of normal cells and which are likely to be unaffected by tumour heterogeneity and genetic instability, could provide particularly relevant targets for anti-cancer drug development.
Warenius
Hilmar M
HM
University of Liverpool, Oncology Research Unit, Dept. of Medicine, University Clinical Departments, Duncan Building, Daulby Street, Liverpool, L69 3GA, U.K.
D002455:Cell Division / Q000235:genetics; D015195:Drug Design; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D009363:Neoplasm Proteins