title: Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.
abstract: Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors.Cancer Res; 77(10); 2712-21. ©2017 AACR.
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanizaki
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Paranal
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hideki
authors.initials: H
authors.lastname: Endoh
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christine
authors.initials: C
authors.lastname: Lydon
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Repellin
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Choi
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ogino
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Redig
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Magda
authors.initials: M
authors.lastname: Bahcall
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Oxnard
authors.affiliation: Department of Cancer Biology, Harvard Medical School, Boston, Massachusetts.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts. pasi_janne@dfci.harvard.edu.|Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003062:Codon; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D016254:Mutagenesis, Insertional; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases