Afatinib restrains K-RAS-driven lung tumorigenesis
- 20 June 2018
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 10 (446)
- https://doi.org/10.1126/scitranslmed.aao2301
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 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.Funding Information
- Austrian Science Fund (FWF-P25599-B19)
- Austrian Science Fund (SFB-F4707)
- Austrian Science Fund (SFB-F06105)
- Fellinger Krebsforschungsverein
- National Research, Development and Innovation Office, Hungary (NVKP_16-1-2016-0037)
- Hungarian NRDI Office (K109626)
- Hungarian NRDI Office (K108465)
- Hungarian NRDI Office (KNN121510)
- Hungarian NRDI Office (SNN114490)
- Hungarian Academy of Science
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