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In this issue of Cancer Discovery, AI-Ahmadie and colleagues identify a somatic mutation in the RAD50 gene as a likely contributing factor to an unusual curative response to systemic combination therapy employing the DNA-damaging agent irinotecan and a checkpoint kinase 1 inhibitor in a patient with recurrent, metastatic small-cell cancer. This study highlights the importance of in-depth analysis of exceptional responders to chemotherapy and targeted therapy in early-phase clinical trials and opens new avenues for developing cancer genome-based combination therapy to improve the efficacy of traditional chemotherapy through synthetically lethal interactions.

RADical Response Puts an Exceptional Responder in CHKmate: A Synthetic Lethal Curative Response to DNA-Damaging Chemotherapy?