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Sci Transl Med. 2018 Jun 20;10(446). pii: eaao2301. doi: 10.1126/scitranslmed.aao2301.

Afatinib restrains K-RAS-driven lung tumorigenesis.

Author information

1
Department of Physiology, Center of Physiology and Pharmacology and Comprehensive Cancer Center (CCC), Medical University of Vienna, AT-1090 Vienna, Austria.
2
Ludwig Boltzmann Institute for Cancer Research, AT-1090 Vienna, Austria.
3
Spanish National Cancer Research Centre, E-28029 Madrid, Spain.
4
Institute of Pathology, Medical University of Graz, AT-8036 Graz, Austria.
5
Division of Thoracic Surgery, Department of Surgery and CCC, Medical University of Vienna, AT-1090 Vienna, Austria.
6
Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, AT-1090 Vienna, Austria.
7
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, AT-1030 Vienna, Austria.
8
Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, ON-M5G 1X5 Toronto, Ontario, Canada.
9
Department of Molecular Genetics, University of Toronto, ON-M5S 1A8 Toronto, Ontario, Canada.
10
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, AT-1210 Vienna, Austria.
11
Medical University of Vienna, AT-1090 Vienna, Austria.
12
Institute of Cancer Research, Medical University of Vienna and CCC, AT-1090 Vienna, Austria.
13
Department of Tumor Biology, National Korányi Institute of Pulmonology, Semmelweis University, HU-1122 Budapest, Hungary.
14
First Department of Pathology and Experimental Cancer Research, Semmelweis University, HU-1122 Budapest, Hungary.
15
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, AT-1090 Vienna, Austria.
16
MTA TK Lendület Cancer Biomarker Research Group, Institute of Enzymology and Second Department of Pediatrics, Semmelweis University, HU-1122 Budapest, Hungary.
17
Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, HU-1122 Budapest, Hungary.
18
Department of Physiology, Center of Physiology and Pharmacology and Comprehensive Cancer Center (CCC), Medical University of Vienna, AT-1090 Vienna, Austria. emilio.casanova@meduniwien.ac.at.

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.

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