An oligoclonal antibody durably overcomes resistance of lung cancer to third-generation EGFR inhibitors

Autor: Hilah Gal, Georg Mahlknecht, Luigi Mazzeo, Julian Downward, Tomer-Meir Salame, Yehoshua Enuka, Donatella Romaniello, Moshit Lindzen, Dominick G. A. Burton, Maicol Mancini, Emilie Bousquet, Dan Adreka, Raya Eilam Altstadter, Nadège Gaborit, Antonio Maraver, Ashish Noronha, Valery Krizhanovsky, Yosef Yarden, Ilaria Marrocco, Lee Roth
Přispěvatelé: Department of Biological Regulation [Rehovot, Israel], Weizmann Institute of Science [Rehovot, Israël], Department of Molecular Cell Biology [Rehovot], Department of Biological Services [Rehovot, Israel], Department of Veterinary Resources [Rehovot, Israel], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), The Francis Crick Institute [London], The institute of cancer research [London], Our laboratory was supported by the European Research Council, the Israel Science Foundation, the Seventh Framework Program of the European Commission (LungTarget Consortium), the Israel Cancer Research Fund and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation., Herrada, Anthony, Mancini M, Gal H, Gaborit N, Mazzeo L, Romaniello D, Salame TM, Lindzen M, Mahlknecht G, Enuka Y, Burton DG, Roth L, Noronha A, Marrocco I, Adreka D, Altstadter RE, Bousquet E, Downward J, Maraver A, Krizhanovsky V, Yarden Y
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Medicine (General)
Lung Neoplasms
Respiratory System
Cetuximab
QH426-470
NSCLC
T790M
Piperazines
Antineoplastic Agents
Immunological
0302 clinical medicine
Trastuzumab
Carcinoma
Non-Small-Cell Lung
Medicine
Osimertinib
Epidermal growth factor receptor
Research Articles
Cancer
EGFR inhibitors
Settore BIO/11 - BIOLOGIA MOLECOLARE
Aniline Compounds
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
apoptosis
3. Good health
ErbB Receptors
030220 oncology & carcinogenesis
Molecular Medicine
Immunotherapy
Research Article
medicine.drug
medicine.drug_class
kinase inhibitor
[SDV.CAN]Life Sciences [q-bio]/Cancer
Monoclonal antibody
03 medical and health sciences
R5-920
[SDV.CAN] Life Sciences [q-bio]/Cancer
Genetics
Humans
Pharmacology & Drug Discovery
Lung cancer
Protein Kinase Inhibitors
antibody therapy
Acrylamides
business.industry
medicine.disease
apoptosi
030104 developmental biology
Drug Resistance
Neoplasm
Mutation
Cancer research
biology.protein
business
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: EMBO Molecular Medicine, Vol 10, Iss 2, Pp 294-308 (2018)
EMBO Molecular Medicine
EMBO Molecular Medicine, Wiley Open Access, 2018, 10 (2), pp.294-308. ⟨10.15252/emmm.201708076⟩
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201708076⟩
Popis: International audience; Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors. We now report that 3×mAbs, including a triplet containing cetuximab and trastuzumab, inhibits C797S-expressing tumors. Unlike osimertinib, which induces apoptosis, 3×mAbs promotes degradation of the three receptors and induces cellular senescence. Consistent with distinct mechanisms, treatments combining 3×mAbs plus sub-inhibitory doses of osimertinib synergistically and persistently eliminated tumors. Thus, oligoclonal antibodies, either alone or in combination with kinase inhibitors, might preempt repeated cycles of treatment and rapid emergence of resistance.
Databáze: OpenAIRE
Externí odkaz: