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

Abstract

Purpose: 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.Experimental Design: 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 fusion) 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 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 CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth.Conclusions: 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.

Phase 1 Dose Escalation Study of Seribantumab (MM-121), an anti-HER3 Monoclonal Antibody, in Patients with Advanced Solid Tumors

“…xenograft models of various tumor types, including lung, ovarian and pancreatic tumors harboring different NRG1 fusions and, therefore, support clinical investigations of seribantumab in patients with these types of tumors [9].…”

“…This expansion of knowledge has led to a rational adjustment in the seribantumab clinical development program, setting focus on solid tumors driven by NRG1 fusions [9,20]. Data from preclinical studies to date demonstrate encouraging antitumor activity of seribantumab in cancer cell lines and patient-derived…”

“…Homo-or heterodimerization between members of the ERBB family leads to activation of downstream signaling pathways mediating tumor growth, survival and differentiation [2,3].The most potent dimerization occurs between HER2 and HER3, which results in enhanced signal transduction compared with other ERBB family dimers [4] Elevated expression of HER3 is seen in many solid tumors, including lung, colorectal, breast and ovarian cancers, and is typically associated with poor prognosis [4][5][6][7] Seribantumab (formerly MM-121), a fully human immunoglobulin G2 anti-HER3 monoclonal antibody, was initially developed for the treatment of solid tumors in which HER3 signaling is active [8]. In recent in vitro studies, seribantumab has been shown to block ligand-dependent activation of HER3, HER2-HER3 dimerization, and, to a lesser extent, dimerization with other ERBB family members [9] Of note, in tumor models harboring NRG1 fusions, seribantumab leads to reduced phosphorylation across the ERBB family and subsequent inhibition of downstream signaling pathways, including the phosphoinositide 3-kinase protein kinase B and mitogen-activated protein kinase pathways, resulting in the inhibition of cancer cell survival [9] Here we present the safety, e cacy and pharmacokinetic (PK) outcomes from a Phase 1 study of seribantumab monotherapy in patients with solid tumors (NCT00734305), which provide a foundation for subsequent seribantumab studies.…”

Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

“…4). This observation was further validated by blocking HER3 with seribantumab, a humanized HER3-speci c antibody that demonstrated signi cant HER3 inhibition in previous studies 22,23,30 . We found that seribantumab completely blocked EC-induced HER3 and AKT phosphorylation in all cell lines we used (Fig.…”

“…Then we used CRC cell lines and demonstrated that liver ECs activated the HER3-AKT signaling pathway and increased CRC cells growth and resistance to 5-FU regardless of the KRAS mutation status. Moreover, the EC-induced pro-survival effects on CRC cells were completely blocked by HER3 siRNA knockdown, or with the HER3 antibody seribantumab that was used in preclinical and clinical studies [22][23][24] . Lastly, we used an orthotopic liver injection xenograft model and determined that blocking HER3 with seribantumab decreased CRC tumor growth and sensitized CRC to 5-FU chemotherapy.…”