title: HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
abstract: EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Takezawa
authors.forename: Valentina
authors.initials: V
authors.lastname: Pirazzoli
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Nebhan
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Spitzler
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Melnick
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000077716:Afatinib; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human