title: Activating HER2 mutations in HER2 gene amplification negative breast cancer.
abstract: Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.
  
  
  CONCLUSIONS
  We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. rbose@dom.wustl.edu
authors.forename: Ron
authors.initials: R
authors.lastname: Bose
authors.forename: Shyam M
authors.initials: SM
authors.lastname: Kavuri
authors.forename: Adam C
authors.initials: AC
authors.lastname: Searleman
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.forename: John
authors.initials: J
authors.lastname: Monsey
authors.forename: Nicholas
authors.initials: N
authors.lastname: Goel
authors.forename: Adam B
authors.initials: AB
authors.lastname: Aronson
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib