Highlights d Comprehensive LUAD proteogenomics exposes multi-omic clusters and immune subtypes d Phosphoproteomics identifies candidate ALK-fusion diagnostic markers and targets d Candidate drug targets: PTPN11 (EGFR), SOS1 (KRAS), neutrophil degranulation (STK11) d Phospho and acetyl modifications denote tumor-specific markers and druggable proteins

Highlights d Unsupervised clustering revealed subtype with EMT and phosphoprotein signatures d Potential therapeutic vulnerabilities included survivin, NSD3, LSD1, and EZH2 d Rb phosphorylation nominated as a biomarker for trials with CDK4/6 inhibitors d Detailed immune landscape analysis highlighted targetable points of immuneregulation

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pre-treatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis and fatty acid metabolism, that were resistance-associated. Both proteomics and transcriptomics revealed sensitivity was marked by elevation of DNA repair, E2F targets, G2M checkpoint, interferon-gamma signaling and immune checkpoint components. Proteogenomic analyses of somatic copy number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1 and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathological complete response, higher chromosomal instability (CIN) and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC pre-clinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications.