Afatinib restrains K-RAS-driven lung tumorigenesis
| Autor: | Julian Mohrherr, Helmut Popper, Emilio Casanova, Monica Musteanu, Katalin Dezso, Klemens Pranz, Maria Sibilia, Daniel Schramek, Herwig P. Moll, Balázs Győrffy, Petra Aigner, Mariano Barbacid, Dagmar Stoiber, Balazs Dome, Pedro P. López-Casas, Richard Moriggl, Beatrice Grabner, Robert Eferl, Judit Moldvay, Viktoria Laszlo, Natascha Hruschka, Luka Brcic, Patricia Stiedl, Manuel Hidalgo, Josef M. Penninger |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Carcinogenesis Afatinib Cell Viral Oncogene Adenocarcinoma of Lung medicine.disease_cause Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Erlotinib Hydrochloride ErbB Cell Line Tumor medicine Humans Epidermal growth factor receptor Cell Proliferation biology Gefitinib General Medicine respiratory tract diseases ErbB Receptors 030104 developmental biology medicine.anatomical_structure Cell culture Drug Resistance Neoplasm Mutation Cancer research biology.protein Tyrosine kinase medicine.drug Signal Transduction |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 |
| Popis: | On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth. However, EGFR inhibition initiates a rapid resistance mechanism involving non-EGFR ERBB family members. This tumor escape mechanism clarifies the disappointing outcome of first-generation TKIs and suggests high therapeutic potential of pan-ERBB inhibitors. On the basis of various experimental models including genetically engineered mouse models, patient-derived and cell line-derived xenografts, and in vitro experiments, we demonstrate that the U.S. Food and Drug Administration-approved pan-ERBB inhibitor afatinib effectively impairs K-RAS-driven lung tumorigenesis. Our data support reconsidering the use of pan-ERBB inhibition in clinical trials to treat K-RAS-mutated NSCLC. |
| Databáze: | OpenAIRE |
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