| Summary: | The notion that targeted drugs can unplug gain-of-function tumor pathways has revitalized pharmaceutical research, but the survival benefits of this strategy have so far proven modest. A weakness of oncogene-blocking approaches is that they do not address the problem of cancer progression as selected by the recessive phenotypes of genetic instability and apoptotic resistance which in turn arise from loss-of-function - i.e., undruggable - defects of caretaker (e.g., BRCA, MLH1) or gatekeeper (e.g., TP53, PTEN) suppressor genes. Genetic instability ensures that rapid cell kill is balanced by similarly rapid selection for apoptotic resistance and hence for metastasis; doubt is thus cast on the assumption that cytotoxicity ('response') is the best way to identify survival-enhancing drugs. In the absence of gene therapy, it is proposed here that caretaker-defective (high-instability) tumors may be best treated with low-lethality drugs inducing replicative (RAS-RAF-ERK) arrest or dormancy, causing 'stable disease' rather than tumorilytic remission. Gatekeeper-defective (death-resistant) tumors, on the other hand, may be best managed by combining survival (PI3K-AKT-mTOR) pathway blockade with metronomic or sequential pro-apoptotic drugs.
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