ScienceWeek

CELL BIOLOGY: ON GENE MUTATIONS AND CANCER CELLS

The following points are made by William G. Kaelin (Nature 2006 441:32):

1) Cancer arises when the right combination of genes is mutated in a susceptible cell, much like lock tumblers falling into place. These mutations bestow various properties of malignancy upon the cell, such as independence from growth control and the ability to colonize other tissues. The fact that such cells contain multiple gene mutations tends to be viewed as problematic by developers of anticancer treatments -- the typical thinking goes that each mutation is beneficial to the cancer cell and makes it hardier. But the mutations probably come at a cost to the cell with respect to its ability to respond to certain situations. Unfortunately, we cannot yet predict how cancer-associated mutations might make a cell vulnerable, and there have been no unbiased methods for systematically discovering these weaknesses. New work [1], however, describes an approach for identifying genes that become essential for the survival of cancer cells.

2) The idea that the deleterious consequences of a particular mutation might be revealed only under specific conditions is an old one. Not surprisingly, it has been most extensively explored in organisms such as yeast and fruitflies, in which the genome can be manipulated easily and the consequent changes seen rapidly. Such investigations uncovered a gene-gene interaction, called "synthetic lethality", which has potential significance for cancer drug discovery. Two genes (A and B, say) are said to be synthetically lethal if the cell containing them dies when both genes are mutated, but it can survive if either gene alone is mutated. In perhaps the simplest case, A and B perform the same function and are uniquely redundant with respect to one another. Alternatively, B might be part of a pathway that can "rescue" the pathway that is damaged by mutation of A. Studies in yeast, however, suggest that these possibilities are the tip of the iceberg -- synthetic-lethal interactions seem to be unexpectedly common, although they are often hard to predict [2,3].

3) Hartwell et al [4] proposed that synthetic-lethal interactions could be used to develop safer and more effective anticancer drugs. In particular, they considered the case of tumor-suppressor genes, the protein products of which inhibit tumor growth, and which are often inactivated in cancers by mutations. A drug that inhibits the protein product of a gene that is synthetically lethal to a tumor-suppressor gene would, by definition, kill those cells in which the tumor-suppressor gene was inactivated, but not their normal counterparts.

4) This approach is conceptually appealing because it turns cancer-specific mutations into a liability for the cells that contain them. It also tackles two vexing problems in cancer drug discovery: how to kill cancer cells without harming normal cells, and how to tackle "loss-of-function" mutations pharmacologically: most effective drugs cause a loss of function, rather than restoring a damaged function. Synthetic lethality typically involves two loss-of-function mutations, but it also applies to gain-of-function mutations -- those making an enzyme permanently active, say. For example, a gain of function in A might be synthetically lethal if it is not tolerated when B is inactive. In the jargon of cancer biology, genes that contribute to cancer when carrying gain-of-function mutations are termed proto-oncogenes, and one can envision other targets that might become vital to the cell specifically in the context of such proto-oncogene mutations.

References (abridged):

1. Ngo, V. N. et al. Nature 441, 106-110 (2006)

2. Sharom, J. R. , Bellows, D. S. & Tyers, M. Curr. Opin. Chem. Biol. 8, 81-90 (2004)

3. Kaelin, W. G. Nature Rev. Cancer 5, 689-698 (2005)

4. Hartwell, L. , Szankasi, P. , Roberts, C. , Murray, A. & Friend, S. Science 278, 1064-1068 (1997)

5. Willingham, A. T. , Deveraux, Q. L. , Hampton, G. M. & Aza-Blanc, P. Oncogene 23, 8392-8400 (2004)

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