Show simple item record Moll HP Pranz K Musteanu M Grabner B Hruschka N Mohrherr J Aigner P Stiedl P Brcic L Laszlo, Viktoria Schramek D Moriggl R Eferl R Moldvay, Judit Dezső, Katalin Lopez-Casas PP Stoiber D Hidalgo M Penninger J Sibilia M Győrffy, Balázs Barbacid M Döme, Balázs Popper H Casanova E 2020-06-05T08:18:01Z 2020-06-05T08:18:01Z 2018
dc.identifier 85048869595
dc.identifier.citation journalVolume=10;journalIssueNumber=446, pages: 12;journalTitle=SCIENCE TRANSLATIONAL MEDICINE;journalAbbreviatedTitle=SCI TRANSL MED;
dc.identifier.uri doi:10.1126/scitranslmed.aao2301
dc.description.abstract 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.
dc.relation.ispartof urn:issn:1946-6234
dc.title Afatinib restrains K-RAS-driven lung tumorigenesis
dc.type Journal Article 2019-03-06T10:06:27Z
dc.language.rfc3066 en
dc.rights.holder NULL
dc.identifier.mtmt 3388794
dc.identifier.wos 000435829300001
dc.identifier.pubmed 29925635
dc.contributor.department SE/AOK/K/Pulmonológiai Klinika
dc.contributor.department SE/AOK/I/I. Sz. Patológiai és Kísérleti Rákkutató Intézet
dc.contributor.department SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika
dc.contributor.department SE/AOK/K/Mellkassebészeti Klinika
dc.contributor.institution Semmelweis Egyetem

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