We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Afatinib restrains K-RAS-driven lung tumorigenesis.
- Authors
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; Dezso, Katalin; Lopez-Casas, Pedro P.; Stoiber, Dagmar; Hidalgo, Manuel; Penninger, Josef; Sibilia, Maria
- Abstract
K-RAS–mutated lung adenocarcinomas depend on ERBB signaling, and pan-ERBB inhibitors impair K-RAS–driven lung tumorigenesis. A new role for kinase inhibitors: The K-RAS oncogene is frequently mutated in a variety of cancer types, including lung cancer. Lung cancers with K-RAS mutations are usually difficult to target, and conventional thinking dictates that these tumors are resistant to receptor tyrosine kinase inhibitors because those act upstream of the constitutively active K-RAS protein. However, it appears that receptor tyrosine kinase signaling may have an effect on K-RAS–driven lung tumors after all, by amplifying their growth beyond the effects of K-RAS alone. Kruspig et al. and Moll et al. independently reached this conclusion and identified approved multikinase inhibitors that are effective in the setting of K-RAS–mutant lung cancer in multiple mouse models, suggesting that this may be a potential treatment strategy for human patients as well. 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.
- Subjects
EPIDERMAL growth factor receptors; ERLOTINIB; GEFITINIB; LUNG cancer; ANTINEOPLASTIC agents
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 446, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aao2301