Afatinib restrains K-RAS-driven lung tumorigenesis

作者：Moll Herwig P; Pranz Klemens; Musteanu Monica; Grabner Beatrice; Hruschka Natascha; Mohrherr Julian; Aigner Petra; Stiedl Patricia; Brcic Luka; Laszlo Viktoria; Schramek Daniel; Moriggl Richard; Eferl Robert; Moldvay Judit; Derso Katalin; Lopez Casas Pedro P; Stoiber Dagmar; Hidalgo Manuel; Penninger Josef; Sibilia Maria; Gyorffy Balazs; Barbacid Mariano; Dome Balazs; Popper Helmut; Casanova Emilio^*

来源：Science Translational Medicine, 2018, 10(446): eaao2301.

DOI：10.1126/scitranslmed.aao2301

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.

• 出版日期2018-6-20