Afatinib restrains K-RAS-driven lung tumorigenesis

Autor:in

Moll, Herwig; Pranz, Klemens; Musteanu, Monica; Grabner, B.; Hruschka, N.; Mohrherr, Julian; Aigner, Petra; Stiedl, Patricia; Brcic, Luka; laszlo, viktoria; Schramek, Daniel; Moriggl, Richard; Eferl, Robert; Moldvay, Judit; Derso, Katalin; Lopez-Casas, Pedro; Stoiber, Dagmar; Hidalgo, Manuel; Penninger, Josef; Sibilia, Maria; Gyorffy, Balazs; Barbacid, Mariano; Doeme, Balazs; Popper, Helmut; Casanova, Emilio

Abstrakt

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 Egfrquenches 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.

Dokumententyp

Originalarbeit

DOI

10.1126/scitranslmed.aao2301

PubMed ID

MEDLINE:29925635