Data from 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

&lt;div&gt;AbstractPurpose:&lt;p&gt;Oncogenic fusions involving the &lt;i&gt;neuregulin 1&lt;/i&gt; (&lt;i&gt;NRG1&lt;/i&gt;) 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.&lt;/p&gt;Experimental Design:&lt;p&gt;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 &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;.&lt;/p&gt;Results:&lt;p&gt;Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, &lt;i&gt;DOC4-NRG1&lt;/i&gt; fusion) and lung (LUAD-0061AS3, &lt;i&gt;SLC3A2-NRG1&lt;/i&gt; fusion) cancer cells harboring &lt;i&gt;NRG1&lt;/i&gt; fusions or &lt;i&gt;NRG1&lt;/i&gt; amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a &lt;i&gt;CD74-NRG1&lt;/i&gt; 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 &lt;i&gt;CLU-NRG1&lt;/i&gt; fusion) PDX tumors induced regression of tumors by 50%–100%. Afatinib was much less effective at blocking tumor growth.&lt;/p&gt;Conclusions:&lt;p&gt;Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of &lt;i&gt;NRG1&lt;/i&gt; fusion–dependent tumorigenesis &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; in breast, lung, and ovarian patient-derived cancer models.&lt;/p&gt;&lt;/div&gt;