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

Abstract

Oncogenic fusions involving the <i>neuregulin 1</i> (<i>NRG1</i>) 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 <i>in vitro</i> and <i>in vivo</i>. Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, <i>DOC4-NRG1</i> fusion) and lung (LUAD-0061AS3, <i>SLC3A2-NRG1</i> fusion) cancer cells harboring <i>NRG1</i> fusions or <i>NRG1</i> amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a <i>CD74-NRG1</i> 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 <i>CLU-NRG1</i> 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 <i>NRG1</i> fusion-dependent tumorigenesis <i>in vitro</i> and <i>in vivo</i> in breast, lung, and ovarian patient-derived cancer models.