title: ErbB-3 activation by NRG-1β sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells (CSCs).
abstract: Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome. Vice versa, targeted inhibition of BRAF-V600E with the selective inhibitor PLX 4032 (Vemurafenib) is severely limited due to feedback re-activation of EGFR in these tumors. Mounting evidence indicates that upregulation of the ErbB-3 signaling axis may occur in response to several targeted therapeutics, including Vemurafenib, and NRG-1β-dependent re-activation of the PI3K/AKT survival pathway has been associated with therapy resistance.Here we show that colon CSCs express, next to EGFR and ErbB-2, also significant amounts of ErbB-3 on their membrane. This expression is functional as NRG-1β strongly induces AKT/PKB and ERK phosphorylation, cell proliferation, clonogenic growth and promotes resistance to Vemurafenib in BRAF-V600E mutant colon CSCs. This resistance was completely dependent on ErbB-3 expression, as evidenced by knockdown of ErbB-3. More importantly, resistance could be alleviated with therapeutic antibody blocking ErbB-3 activation, which impaired NRG-1β-driven AKT/PKB and ERK activation, clonogenic growth in vitro and tumor growth in xenograft models. In conclusion, our findings suggest that targeting ErbB-3 receptors could represent an effective therapeutic approach in BRAF-V600E mutant colon cancer.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.|Cancer Genomics Center, The Netherlands.
authors.forename: Pramudita R
authors.initials: PR
authors.lastname: Prasetyanti
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.
authors.forename: Emily
authors.initials: E
authors.lastname: Capone
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barcaroli
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Agostino
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Volpe
authors.affiliation: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Benfante
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.|Cancer Genomics Center, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: van Hooff
authors.affiliation: Department of Gynecology and Obstetrics, La Sapienza University of Rome, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iacobelli
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.
authors.forename: Cosmo
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.|MediaPharma s.r.l., Chieti, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.|Cancer Genomics Center, The Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Laurenzi
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, Centro Studi sull'Invecchiamento, Ce.S.I., Chieti, Italy.|MediaPharma s.r.l., Chieti, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sala
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C094131:NRG1 protein, human; D020890:Neuregulin-1; D013449:Sulfonamides; D000077484:Vemurafenib; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: ErbB-3; NRG-1β; colon cancer stem cells; vemurafenib