Afatinib restrains K-RAS-driven lung tumorigenesis

Herwig P. Moll, Klemens Pranz, Monica Musteanu, Beatrice Grabner, Natascha Hruschka, Julian Mohrherr, Petra Aigner, Patricia Stiedl, Luka Brcic, Viktoria Laszlo, Daniel Schramek, Richard Moriggl, Robert Eferl, Judit Moldvay, Katalin Dezso, Pedro P. Lopez-Casas, Dagmar Stoiber, Manuel Hidalgo, Josef Penninger, Maria SibiliaBalázs Gyorffy, Mariano Barbacid, Balázs Dome, Helmut Popper, Emilio Casanova*

*Korrespondierende:r Autor:in für diese Arbeit

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

94 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummeraao2301
FachzeitschriftScience Translational Medicine
Jahrgang10
Ausgabenummer44
DOIs
PublikationsstatusVeröffentlicht - 20 Juni 2018
Extern publiziertJa

ASJC Scopus Sachgebiete

  • Allgemeine Medizin

Fingerprint

Untersuchen Sie die Forschungsthemen von „Afatinib restrains K-RAS-driven lung tumorigenesis“. Zusammen bilden sie einen einzigartigen Fingerprint.

Dieses zitieren