Mutation load, functional overlap, and synthetic lethality in the evolution and treatment of cancer.
The efficacy of conventional anti-cancer drugs is puzzling in view of the ubiquitous tissue distribution and vital nature of their targets. Differences in cell cycling rates are not thought sufficient to explain chemotherapeutic selectivity. I suggest an alternative possibility based on the combinatorial effects of mutations in cancer cells. This model incorporates the concepts of synthetic-lethal interactions and mutation loads to explain the drug sensitivity of cancer cells. From this perspective, drugs that target complex processes that utilize genetically redundant or overlapping components, such as DNA replication and chromosome segregation, offer attractive target opportunities.
Kamb
Alexander
A
Deltagen Proteomics, Inc., 615 Arapeen Drive, Suite 300, Salt Lake City, UT 84108, USA. akamb@deltagenpro.com
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity*; D020090:Chromosome Segregation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D008957:Models, Genetic; D016296:Mutagenesis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome