title: BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma.
abstract: Based on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM), two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05-10). However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance. The multidomain proapoptotic protein BAK, but not its orthologue BAX, was found to be essential for bortezomib-induced apoptosis in MPM cell lines. Immunohistochemistry was performed on tissues from the ICORG-05 phase II trial and a TMA of archived mesotheliomas. Loss of BAK was found in 39% of specimens and loss of both BAX/BAK in 37% of samples. However, MPM tissues from patients who failed to respond to bortezomib and MPM cell lines selected for resistance to bortezomib conserved BAK expression. In contrast, c-Myc dependent transactivation of NOXA was abrogated in the resistant cell lines. In summary, the block of mitochondrial apoptosis is a limiting factor for achieving efficacy of bortezomib in MPM, and the observed loss of BAK expression or NOXA transactivation may be relevant mechanisms of resistance in the clinic.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Busacca
authors.forename: Alex D
authors.initials: AD
authors.lastname: Chacko
authors.forename: Astero
authors.initials: A
authors.lastname: Klabatsa
authors.forename: Kenneth
authors.initials: K
authors.lastname: Arthur
authors.forename: Michael
authors.initials: M
authors.lastname: Sheaff
authors.forename: Dario
authors.initials: D
authors.lastname: Barbone
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.forename: Vignesh K
authors.initials: VK
authors.lastname: Gunasekharan
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Gorski
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Tanani
authors.forename: V Courtney
authors.initials: VC
authors.lastname: Broaddus
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007150:Immunohistochemistry; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001897:Boronic Acids; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib