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

Research output: Contribution to journalArticle

40 Citations (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.

Original languageEnglish
Article numberaao2301
JournalScience Translational Medicine
Volume10
Issue number44
DOIs
Publication statusPublished - Jun 20 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Moll, H. P., Pranz, K., Musteanu, M., Grabner, B., Hruschka, N., Mohrherr, J., Aigner, P., Stiedl, P., Brcic, L., Laszlo, V., Schramek, D., Moriggl, R., Eferl, R., Moldvay, J., Dezso, K., Lopez-Casas, P. P., Stoiber, D., Hidalgo, M., Penninger, J., ... Casanova, E. (2018). Afatinib restrains K-RAS-driven lung tumorigenesis. Science Translational Medicine, 10(44), [aao2301]. https://doi.org/10.1126/scitranslmed.aao2301