title: HER2 activating mutations are targets for colorectal cancer treatment.
abstract: The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs.
  
  
  CONCLUSIONS
  HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Shyam M
authors.initials: SM
authors.lastname: Kavuri
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Naveen
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.affiliation: Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottino
authors.affiliation: Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
authors.forename: Simonetta M
authors.initials: SM
authors.lastname: Leto
authors.affiliation: Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Searleman
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: John
authors.initials: J
authors.lastname: Monsey
authors.affiliation: Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: NSABP Foundation, Pittsburgh, Pennsylvania.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Jacobs
authors.affiliation: Department of Oncology, University of Torino Medical School, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Torino, Italy. National Institute of Biostructures and Biosystems, Rome, Italy. rbose@dom.wustl.edu andrea.bertotti@ircc.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. rbose@dom.wustl.edu andrea.bertotti@ircc.it.
authors.forename: Ron
authors.initials: R
authors.lastname: Bose
mesh_terms: D000077716:Afatinib; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D058990:Molecular Targeted Therapy; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077716:Afatinib; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib