IN THE SPOTLIGHT From Breaking Bad to Worse: Exploiting Homologous DNA Repair Defi ciency in Cancer

Author’s Affi liation: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts Corresponding Author: Michael T. Hemann, The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 76-361B, Cambridge, MA 02139. Phone: 617324-1964; Fax: 617-252-1891; E-mail: [email protected] doi: 10.1158/2159-8290.CD-14-0316 ©2014 American Association for Cancer Research. Summary: DNA repair defi ciencies are common among cancer cells and represent a potential vulnerability that might be exploited by targeting compensatory repair pathways. However, the identifi cation of synthetically lethal combinations of DNA repair defects, although of signifi cant clinical relevance, has been somewhat anecdotal. Although numerous models have been proposed to explain synthetic lethality among DNA repair mutations, we have only a limited understanding of why a given mutation should render cells sensitive to another. In this issue of Cancer Discovery , Dietlein and colleagues defi ne a general connection between mutations in genes involved in homologous recombination and sensitivity to inhibitors of non-homologous end joining. In doing so, they provide a mechanism to demarcate a set of seemingly diverse tumors that may be highly responsive to established DNA repair–targeted therapeutics. Cancer Discov; 4(5); 516–8. ©2014 AACR.