ABSTRACT: Anurag M, Jaehnig EJ, Krug K, Lei JT, Bergstrom EJ, Kim BJ, Vashist TD, Huynh AMT, Dou Y, Gou X, Huang C, Shi Z, Wen B, Korchina V, Gibbs RA, Muzny DM, Doddapaneni H, Dobrolecki LE, Rodriguez H, Robles AI, Hiltke T, Lewis MT, Nangia J, Shafaee MN, Hagemann I, Hoog J, Lim B, Osborne CK, Mani DR, Gillette MA, Zhang B, Echeverria GV, Miles G, Rimawi MF, Carr SA, Ademuyiwa FO, Satpathy S, and Ellis MJ.
Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin & docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pre-treatment biopsies uniquely revealed that metabolic pathways including oxidative phosphorylation, fatty acid metabolism and glycolysis were resistance-associated. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2M checkpoint, interferon-gamma response, and immune checkpoint components. Proteogenomic analyses of somatic copy number aberrations identified a resistance-associated 19q13.32-33 deletion where LIG1, POLD1 and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I involved in lagging strand synthesis) gene deletion and/or low mRNA expression were associated with lack of pathological complete response and poor prognosis in TNBC, as well as selective carboplatin-resistance in TNBC patient-derived xenograft models. Low expression or LIG1 loss was also associated with higher chromosomal instability index (CIN) and poor prognosis in other cancer types, demonstrating that deletion of lagging-strand synthesis components has broad clinical significance.
Steven A. Carr 
