title: Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.
abstract: 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.
authors.affiliation: 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.
authors.forename: Elza C
authors.initials: EC
authors.lastname: de Bruin
authors.forename: Catherine
authors.initials: C
authors.lastname: Cowell
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Warne
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Saunders
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Melnick
authors.forename: Scott
authors.initials: S
authors.lastname: Gettinger
authors.forename: Zenta
authors.initials: Z
authors.lastname: Walther
authors.forename: Anna
authors.initials: A
authors.lastname: Wurtz
authors.forename: Guus J
authors.initials: GJ
authors.lastname: Heynen
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Javier
authors.initials: J
authors.lastname: Gómez-Román
authors.forename: Almudena
authors.initials: A
authors.lastname: García-Castaño
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D009374:Neoplasms, Experimental; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D025542:Neurofibromin 1; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D000069347:Erlotinib Hydrochloride