A cardinal feature of cancer cells is the deregulation of cell cycle controls. Targeted drug therapy is designed to take advantage of specific genetic alterations that distinguish tumor cells from their normal counterparts. Mutated oncogenes and inactivated tumor suppressors can increase the dependency of cancer cells on G-phase cyclin-dependent kinases, augment replication stress and DNA damage during S phase, and dismantle checkpoints that monitor progression through S/G/M. These acquired defects generate cancer cell–specific vulnerabilities that provide a window of opportunity for targeted cancer treatments. We review the basic principles underlying the design of targeted therapies with emphasis on two main features: oncogene addiction and synthetic lethality. We discuss how traditional cytotoxic agents may depend, with relatively less specificity, on these same features and then point to examples of the successful application of newly developed, targeted therapeutic agents that offer reduced, dose-limiting toxicities to normal cells.


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