Odintsov et al., Clinical Cancer Research 2021
OnlineFirst version published April 6, 2021 (Open Access)
Abstract
Background. Oncogenic fusions involving the neuregulin 1 (NRG1) 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.
Methods. 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 in vitro and in vivo.
Results. Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of pro-apoptotic 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 PDX and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50–100%. Afatinib was much less effective at blocking tumor growth.
Conclusion. Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung and ovarian patient-derived cancer models.