Zenocutuzumab, a HER2XHER3 bispecific antibody, is effective therapy for tumors driven by NRG1 gene rearrangements Journal Article
| Authors: | Schram, A. M.; Odintsov, I.; Espinosa-Cotton, M.; Khodos, I.; Sisso, W. J.; Mattar, M. S.; Lui, A. J. W.; Vojnic, M.; Shameem, S. H.; Chauhan, T.; Torrisi, J.; Ford, J.; O’Connor, M. N.; Geuijen, C. A. W.; Schackmann, R. C. J.; van Bueren, J. J. L.; Wasserman, E.; de Stanchina, E.; O’Reilly, E. M.; Ladanyi, M.; Drilon, A.; Somwar, R. |
| Article Title: | Zenocutuzumab, a HER2XHER3 bispecific antibody, is effective therapy for tumors driven by NRG1 gene rearrangements |
| Abstract: | NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strat-egy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity–enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion–positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion–positive metastatic cancer were treated with Zeno. Two patients with ATP1B1– NRG1–positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74–NRG1-positive non–small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion–positive cancers. © 2022 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | signal transduction; protein kinase b; adult; clinical article; protein phosphorylation; gene mutation; genetics; case report; cisplatin; systemic therapy; capecitabine; gemcitabine; cancer patient; flow cytometry; lymph node dissection; pancreaticoduodenectomy; cell proliferation; biological marker; metabolism; carboplatin; apoptosis; computer assisted tomography; tumor volume; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; epidermal growth factor receptor 2; lung cancer; cytotoxicity; tumor regression; tumor xenograft; enzyme activity; cell line, tumor; protein p53; carcinogenesis; cancer resistance; irinotecan; lung tumor; gene rearrangement; immunoglobulin g; xenograft; bone marrow biopsy; cyclin dependent kinase inhibitor 1b; folinic acid; tumor cell line; western blotting; gene fusion; bleomycin; chimeric antigen receptor; dna fingerprinting; receptor, erbb-2; stereotactic radiosurgery; tumor growth; estrogen receptor; trastuzumab; epidermal growth factor receptor 3; cyclin d1; k ras protein; pemetrexed; lobectomy; liver biopsy; b raf kinase; amylase; antibody dependent cellular cytotoxicity; carfilzomib; rna sequence; programmed death 1 ligand 1; cyclin dependent kinase 6; non small cell lung cancer; neu differentiation factor; neuregulin-1; wedge resection; receptor, erbb-3; antibodies, bispecific; cd74 antigen; afatinib; chemoluminescence; bispecific antibody; tumor spheroid; humans; human; female; article; pembrolizumab; lung cancer cell line; erdheim chester disease; breast cancer cell line; ic50; mtt assay; whole exome sequencing; osimertinib; sk-br-3 cell line; zenocutuzumab; nrg1 protein, human; chromium release assay |
| Journal Title: | Cancer Discovery |
| Volume: | 12 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-05-01 |
| Start Page: | 1233 |
| End Page: | 1247 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-21-1119 |
| PUBMED: | 35135829 |
| PROVIDER: | scopus |
| PMCID: | PMC9394398 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2022 -- Source: Scopus |
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