In this study, we aim to determine the prevalence of somatic deletions of RB1 and NUDT15 across various cancer types, and to evaluate the metabolic vulnerability caused by NUDT15 deletion in cell lines and mouse models, which will shed light on a possible 6MP‐based collateral lethality and drug repurposing strategy for treating cancers with somatic RB1–NUDT15 deletion. Here, RB1 is linked to cancer.