title: Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer.
abstract: Incurable castration-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) activation. Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease. In this study, we investigated one mechanism of ENZ resistance, and tried to improve therapeutic efficiency of ENZ. We found HER2 expression is increased in ENZR tumors and cell lines, and is induced by ENZ treatment of LNCaP cells. ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity. HER2 dependent AR activation in LNCaP and ENZR cells was effectively blocked by treatment with the EGFR/HER2 inhibitor Lapatinib, which reduced cell viability and increased apoptosis. Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth. However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC. These results suggest that while HER2 overexpression and subsequent AR activation is a targetable mechanism of resistance to ENZ, therapy using Lapatinib is only a rational therapeutic approach when used in combination with ENZ in CRPC.
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Masaki
authors: M
authors: Shiota
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Jennifer L
authors: JL
authors: Bishop
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ario
authors: A
authors: Takeuchi
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ka Mun
authors: KM
authors: Nip
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Thomas
authors: T
authors: Cordonnier
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Eliana
authors: E
authors: Beraldi
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Hidetoshi
authors: H
authors: Kuruma
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Martin E
authors: ME
authors: Gleave
authors: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Amina
authors: A
authors: Zoubeidi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011944:Receptors, Androgen / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors*
chemical_list: D059002:Androgen Receptor Antagonists; D001549:Benzamides; D066246:ErbB Receptors; D000077341:Lapatinib; D009363:Neoplasm Proteins; D009570:Nitriles; D010669:Phenylthiohydantoin; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D051840:Y-Box-Binding Protein 1; C410798:AR protein, human; C070856:YBX1 protein, human; C540278:enzalutamide; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C494918:AKT1 protein, human
keywords: HER2; castration resistant prostate cancer; enzalutamide; lapatinib