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Cancer Discov. 2014 May;4(5):606-19. doi: 10.1158/2159-8290.CD-13-0741. Epub 2014 Feb 17.

Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.

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1Signal Transduction and 2High Throughput Screening Laboratories, Cancer Research UK London Research Institute; 3The Institute of Cancer Research, London, United Kingdom; 4Yale Cancer Center, Departments of 5Medicine (Medical Oncology), and 6Pathology, Yale University School of Medicine, New Haven, Connecticut; 7Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; 8Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland; 9Division of Molecular Carcinogenesis, The Netherlands Cancer Institute; Departments of 10Pathology and 11Pulmonary Diseases, VU University Medical Center, Amsterdam, the Netherlands; 12Pathology Service, and 13Oncology Service Hospital Universitario Marques de Valdecilla, IFIMAV, Santander, Spain.


Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.

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