Using whole-genome sequencing, Al-Ahmadie, Iyer, Hohl, and colleagues identified a clonal hemizygous RAD50^L1237F mutation in an outlier patient with metastatic small-cell ureter cancer who achieved a complete and durable response to treatment with a checkpoint kinase 1 inhibitor and irinotecan. RAD50^L1237F was accompanied by LOH of the wild-type allele and mutated a highly conserved residue required for proper MRE11 complex function in DNA repair. RAD50 mutation impaired activation of ataxia telangiectasia mutated (ATM) signaling, leading to a synthetic lethal effect when checkpoint inhibition was combined with DNA-damaging chemotherapy. These findings highlight the utility of this approach to dissect tumor-specific dependencies and provide a rationale for combining checkpoint inhibitors with DNA-damaging chemotherapy in patients whose tumors harbor MRE11 complex mutations. For details, please see the article by Al-Ahmadie, Iyer, Hohl, and colleagues on page 1014.