title: Bruton's Tyrosine Kinase Inhibitors Prevent Therapeutic Escape in Breast Cancer Cells.
abstract: We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292, and CGI-1746, reduce breast cancer cell survival and prevent drug-resistant clones from arising. Ibrutinib treatment impacts HER2(+) breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4. Consequently, the activation of AKT and ERK signaling pathways are also blocked leading to a G1-S cell-cycle delay and increased apoptosis. Importantly, inhibition of BTK prevents activation of the AKT signaling pathway by NRG or EGF that has been shown to promote growth factor-driven lapatinib resistance in HER2(+) breast cancer cells. HER2(+) breast cancer cell proliferation is blocked by ibrutinib even in the presence of these factors. AVL-292, which has no effect on EGFR family activation, prevents NRG- and EGF-dependent growth factor-driven resistance to lapatinib in HER2(+) breast cancer cells. In vivo, ibrutinib inhibits HER2(+) xenograft tumor growth. Consistent with this, immunofluorescence analysis of xenograft tumors shows that ibrutinib reduces the phosphorylation of HER2, BTK, Akt, and Erk and histone H3 and increases cleaved caspase-3 signals. As BTK-C and HER2 are often coexpressed in human breast cancers, these observations indicate that BTK-C is a potential therapeutic target and that ibrutinib could be an effective drug especially for HER2(+) breast cancer. Mol Cancer Ther; 15(9); 2198-208. ©2016 AACR.
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York.
authors.forename: Jason
authors.initials: J
authors.lastname: Wong
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sevinsky
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York. Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Kokabee
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York.
authors.forename: Faiza
authors.initials: F
authors.lastname: Khan
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, New York. dconklin@albany.edu.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Conklin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D000077341:Lapatinib; D020890:Neuregulin-1; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C551803:ibrutinib; C000625949:BTK protein, human; C000625951:Btk protein, mouse