synthetic lethality a framework for the development of wiser cancer therapeutics合成杀伤力的框架明智的癌症疗法的发展.pdfVIP

Review Synthetic lethality: a framework for the development of wiser cancer therapeutics William G Kaelin Jr Address: Howard Hughes Medical Institute, Dana­Farber Cancer Institute and Brigham and Women’s Hospital, 44 Binney St, Boston, MA 02115, USA. Email: william_kaelin@ Abstract from high-throughput screens for cytotoxic agents were The challenge in medical oncology has always been to identify historically prioritized using factors such as potency, ease compounds that will kill, or at least tame, cancer cells while of synthesis, drug-like characteristics, structural and leaving normal cells unscathed. Most chemotherapeutic agents mechanistic novelty, and intellectual property considera- in use today were selected primarily for their ability to kill rapidly tions [1]. Although these factors are potentially important, dividing cancer cells grown in cell culture and in mice, with their selectivity determined empirically during subsequent animal and they do not necessarily address selectivity. Sadly, it is human testing. Unfortunately, most of the drugs developed in possible that small molecules capable of selectively killing this way have relatively low therapeutic indices (low toxic dose cancer cells scored in the high-throughput cytotoxicity relative to the therapeutic dose). Recent advances in genomics screens performed over the past 50 years, only to be are leading to a more complete picture of the range of muta­ discarded because they failed one or more of these other tions, both driver and pas