title: Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer.
abstract: Acquired resistance to lapatinib, an inhibitor of EGFR and HER2 kinases, is common. We found that reactivation of EGFR, HER2 and HER3 occurred within 24 hours of lapatinib treatment after their initial dephosphorylation. This was associated with increased expression of NRG1 in cells treated with lapatinib. Exogenous NRG1 partially rescued breast cancer cells from growth inhibition by lapatinib. In addition, both parental and lapatinib-resistant breast cancer cells were sensitive to SGP1, which inhibits binding of NRG1 and other HER3 ligands. Addition of pertuzumab to lapatinib further inhibited NRG1-induced signalling, which was not fully inhibited by either drug alone. In animal model, a combination of pertuzumab to lapatinib induced a greater tumor regression than either lapatinib or pertuzumab monotherapy. This novel combination treatment may provide a promising strategy in clinical HER2-targeted therapy and may inhibit a subset of lapatinib-resistant breast cancer, although the group of patients that will respond to this therapy requires further stratification.
authors.affiliation: Department of Oncology, Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.
authors.forename: Wing-yin
authors.initials: WY
authors.lastname: Leung
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals and Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Roxanis
authors.affiliation: Department of Oncology, Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Sheldon
authors.affiliation: Department of Oncology, Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Department of Oncology, Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.
authors.forename: Ji-liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Department of Oncology, Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Department of Oncology, Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom.|New address: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kong
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020890:Neuregulin-1 / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D020890:Neuregulin-1; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: HER2; NRG1; lapatinib; pertuzumab; resistance