Advancing precision antibody-drug conjugate therapy: unique proteogenomic profiles of tumor subsets in non-small cell lung cancer

Abstract Antibody-drug conjugates (ADCs) represent a promising therapeutic strategy for non-small cell lung cancer (NSCLC), targeting tumor-specific antigens with precision. However, the molecular heterogeneity of NSCLC necessitates multiplex biomarker approaches to optimize ADC efficacy. This study utilized transcriptomics and proteomics to characterize NSCLC subtypes with distinct ADC target expression profiles. RNA-seq data from two independent cohorts (537 tumors, 59 controls; 338 tumors, 311 controls) identified clusters defined by overexpression of CEACAM5, MET, and TACSTD2, while normal lung tissue exhibited moderate TACSTD2 and FOLR1 expression. Chi-squared residual analysis revealed no significant associations with disease stage or driver mutations. Proteomic and transcriptomic data from 110 tumors and 101 controls demonstrated strong concordance. These findings highlight the potential of ADCs to target NSCLC subsets with distinct proteogenomic profiles, independent of disease stage or mutational status, underscoring their broad applicability in precision oncology.