title: Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib.
abstract: HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer. Of note, Dacomitinib, an irreversible small molecule pan-HER inhibitor, was able to completely suppress Δ16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Δ16HER2 activation.
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Tilio
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gambini
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Junbiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Garulli
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Kalogris
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Andreani
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bartolacci
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Elexpuru Zabaleta
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pietrella
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti 66100, Italy.
authors.forename: Albana
authors.initials: A
authors.lastname: Hysi
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti 66100, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.affiliation: Advanced Technology Center for Aging Research, IRCCS-INRCA, Ancona 60121, Italy.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.affiliation: Advanced Technology Center for Aging Research, IRCCS-INRCA, Ancona 60121, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Provinciali
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Ancona 60128, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Galeazzi
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy. Electronic address: cristina.marchini@unicam.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marchini
authors.affiliation: Department of Biosciences and Veterinary Medicine, University of Camerino, Camerino 62032, Italy. Electronic address: augusto.amici@unicam.it.
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008822:Mice, Transgenic; D010641:Phenotype; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D052117:Benzodioxoles; D000077341:Lapatinib; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C525726:dacomitinib; C515233:saracatinib; C508053:ERBB2 protein, human
keywords: Breast cancer; Drug resistances; HER2 isoform; Targeted therapies; Δ16HER2 mice