The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic NRG1 Fusions

• Published in: Clinical cancer research 2021-06, Vol.27 (11), p.3154-3166
• Main Authors: Odintsov, Igor, Lui, Allan J W, Sisso, Whitney J, Gladstone, Eric, Liu, Zebing, Delasos, Lukas, Kurth, Renate I, Sisso, Exequiel M, Vojnic, Morana, Khodos, Inna, Mattar, Marissa S, de Stanchina, Elisa, Leland, Shawn M, Ladanyi, Marc, Somwar, Romel
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-3605

Oncogenic fusions involving the ( ) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion-driven cancers. We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks and . Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, fusion) and lung (LUAD-0061AS3, fusion) cancer cells harboring fusions or amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth. Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of fusion-dependent tumorigenesis and in breast, lung, and ovarian patient-derived cancer models.