Potential of the Synthetic Lethality Principle

Elucidating the first principles of synthetic lethality in cancer, including biological context, will assist clinical translation. Most cancer mutations, including those causing a loss of function, are not directly “druggable” with conventional small-molecule drugs or biologicals, such as antibodies. Thus, despite our growing knowledge of mutations that drive cancer progression, there remains a frustrating gap in translating this information into the development of targeted treatments that kill only cancer cells. An approach that exploits a concept from genetics called “synthetic lethality” could provide a solution. But it has been over 15 years since that framework was proposed (1). Does the synthetic lethality principle still have the potential for treating cancer?

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