Collateral metabolic vulnerabilities unveiled by loss of isozyme diversity in breast cancer.

BACKGROUND: Loss of isozyme diversity (LID) refers to the selective dependency on a single isozyme following the functional collapse of its redundant counterparts, uncovering a metabolic vulnerability. This metabolic liability establishes LID as a novel framework for precision targeting strategy in cancer therapy. METHODS: We integrated a large-scale breast cancer multi-omics cohort to systematically delineate isozyme expression patterns and identify therapeutically promising LID targets across intrinsic molecular subtypes. Genomic and epigenetic data were employed to decipher the underlying causes of LID. Subsequent experiments were conducted to validate the collateral metabolic vulnerabilities arising from identified LID targets and investigate the associated mechanisms. RESULTS: Our analysis delineated the isozyme utilization patterns for metabolic reactions in breast cancer, which revealed widespread and significant LID phenomena. We further decoded the enrichment characteristics of these LID reactions and identified a set of potential clinically relevant LID targets across different subtypes. Further investigation revealed that copy number loss and epigenetic silencing predominantly drive these LIDs, as exemplified by luminal subtype-specific N-myristoyltransferase 2 (NMT2) deficiency caused by hypermethylation. Mechanistic studies demonstrated that NMT2 deficiency confers synthetic lethality with NMT1 inhibition, potentially through impaired myristoylation of the oncogenic effector FMR1 autosomal homolog 2 (FXR2). These findings underscored the potential of NMT inhibitors as viable therapeutic strategies for NMT2-deficient tumors. CONCLUSIONS: In conclusion, this study constructed a comprehensive LID landscape across all breast cancer subtypes, advancing precision oncology through innovative metabolic targeting approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-025-01573-y.