title: Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1.
abstract: Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pirazzoli
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nebhan
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wurtz
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Zenta
authors.initials: Z
authors.lastname: Walther
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Cai
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.affiliation: Antitumor Assessment Core, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Radiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Shapiro
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Gale
authors.affiliation: Program in the Biological and Biomedical Science, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Ruonan
authors.initials: R
authors.lastname: Yin
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Leora
authors.initials: L
authors.lastname: Horn
authors.affiliation: James Thoracic Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, MA 02141, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Gettinger
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: katerina.politi@yale.edu.
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage; D011897:Random Allocation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D046912:Multiprotein Complexes; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000068818:Cetuximab