Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor
| Autor: | Nadège Gaborit, Donatella Romaniello, Belinda Sánchez, Raya Eilam, Diana Drago-Garcia, Ilaria Marrocco, Luis Paz-Ares, Matthew Kreitman, Moshit Lindzen, Gretchen Bergado Báez, Yosef Yarden, Eli Pikarsky, Itay Vaknin, Irene Ferrer, Roni Oren, Nishanth Belugali Nataraj, Soma Ghosh, Jeanette Clarissa Kittel |
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| Přispěvatelé: | Romaniello D, Marrocco I, Belugali Nataraj N, Ferrer I, Drago-Garcia D, Vaknin I, Oren R, Lindzen M, Ghosh S, Kreitman M, Kittel JC, Gaborit N, Bergado Baez G, Sanchez B, Eilam R, Pikarsky E, Paz-Ares L, Yarden Y. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research kinase inhibitor EGFR Context (language use) NSCLC lcsh:RC254-282 Article Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Growth factor receptor Downregulation and upregulation Osimertinib Kinase activity skin and connective tissue diseases Protein kinase B Settore BIO/11 - BIOLOGIA MOLECOLARE drug resistance biology Kinase Chemistry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health body regions lung cancer 030104 developmental biology Oncology monoclonal antibody 030220 oncology & carcinogenesis osimertinib biology.protein Cancer research |
| Zdroj: | Cancers Volume 12 Issue 9 Cancers, Vol 12, Iss 2394, p 2394 (2020) Repisalud Instituto de Salud Carlos III (ISCIII) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12092394 |
| Popis: | 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. Funding: D.R. and I.M. thank the Lombroso Foundation for fellowships. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies are supported by the European Research Council (Oncombine; Grant #740469) and the Dr. Miriam and Sheldon Adelson Medical Research Foundation (Grant #15). Sí |
| Databáze: | OpenAIRE |
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