Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor
Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensa...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-08-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/9/2394 |
| _version_ | 1797555784558575616 |
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| author | Donatella Romaniello Ilaria Marrocco Nishanth Belugali Nataraj Irene Ferrer Diana Drago-Garcia Itay Vaknin Roni Oren Moshit Lindzen Soma Ghosh Matthew Kreitman Jeanette Clarissa Kittel Nadege Gaborit Gretchen Bergado Baez Belinda Sanchez Raya Eilam Eli Pikarsky Luis Paz-Ares Yosef Yarden |
| author_facet | Donatella Romaniello Ilaria Marrocco Nishanth Belugali Nataraj Irene Ferrer Diana Drago-Garcia Itay Vaknin Roni Oren Moshit Lindzen Soma Ghosh Matthew Kreitman Jeanette Clarissa Kittel Nadege Gaborit Gretchen Bergado Baez Belinda Sanchez Raya Eilam Eli Pikarsky Luis Paz-Ares Yosef Yarden |
| author_sort | Donatella Romaniello |
| collection | DOAJ |
| description | Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing. |
| first_indexed | 2024-03-10T16:53:34Z |
| format | Article |
| id | doaj.art-11675062ac2d451c8ec22e88b30f6136 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T16:53:34Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-11675062ac2d451c8ec22e88b30f61362023-11-20T11:13:13ZengMDPI AGCancers2072-66942020-08-01129239410.3390/cancers12092394Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase InhibitorDonatella Romaniello0Ilaria Marrocco1Nishanth Belugali Nataraj2Irene Ferrer3Diana Drago-Garcia4Itay Vaknin5Roni Oren6Moshit Lindzen7Soma Ghosh8Matthew Kreitman9Jeanette Clarissa Kittel10Nadege Gaborit11Gretchen Bergado Baez12Belinda Sanchez13Raya Eilam14Eli Pikarsky15Luis Paz-Ares16Yosef Yarden17Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, SpainDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, 34298 Montpellier, FranceTumor Biology Direction, Center of Molecular Immunology, Havana 11600, CubaTumor Biology Direction, Center of Molecular Immunology, Havana 11600, CubaDepartment of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, IsraelThe Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, SpainDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelAlthough two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.https://www.mdpi.com/2072-6694/12/9/2394drug resistanceEGFRkinase inhibitorlung cancermonoclonal antibodyosimertinib |
| spellingShingle | Donatella Romaniello Ilaria Marrocco Nishanth Belugali Nataraj Irene Ferrer Diana Drago-Garcia Itay Vaknin Roni Oren Moshit Lindzen Soma Ghosh Matthew Kreitman Jeanette Clarissa Kittel Nadege Gaborit Gretchen Bergado Baez Belinda Sanchez Raya Eilam Eli Pikarsky Luis Paz-Ares Yosef Yarden Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor Cancers drug resistance EGFR kinase inhibitor lung cancer monoclonal antibody osimertinib |
| title | Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor |
| title_full | Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor |
| title_fullStr | Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor |
| title_full_unstemmed | Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor |
| title_short | Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor |
| title_sort | targeting her3 a catalytically defective receptor tyrosine kinase prevents resistance of lung cancer to a third generation egfr kinase inhibitor |
| topic | drug resistance EGFR kinase inhibitor lung cancer monoclonal antibody osimertinib |
| url | https://www.mdpi.com/2072-6694/12/9/2394 |
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